Pyrrolo[2,3-d]pyrimidin-4-amine derivative and use thereof in medicine

Abstract

A pyrrolo[2,3-d]pyrimidin-4-amine derivative and a use thereof in medicine, specifically a compound represented by formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a use thereof in the preparation of a drug for treating sGC-related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically discloses a compound represented by formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and the use thereof in the preparation of a drug for treating sGC-related diseases.Background Art

[0002] Nitric oxide (NO) signalling has pleiotropic effects in biology and plays a critical function in cardiovascular homeostasis. An increase in NO secretion occurs under the influence of mediators, such as norepinephrine (NA), angiotensin, adenosine triphosphate, or bradykinin. NO synthesis is also stimulated as a result of numerous physical factors (Int. J. Mol. Sci. 2021, 22, 6029; Molecules 2021, 26, 3418).

[0003] The mechanism of NO's intracellular action is primarily through the stimulation of the activity of soluble guanylyl cyclase (sGC). The sGC is heme-containing enzyme, which causes an increase in the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vascular relaxation (Nat. Rev. Cardiol. 2018, 15,292-316). The NO / sGC / cGMP regulatory pathway plays a leading role in the homeostasis of the cardiovascular and pulmonary systems and organs (such as the kidney, brain, and liver). In addition to smooth muscle cells, cGMP influences the function of fibroblasts, cardiomyocytes, platelets, neurons, and immune cells, regulating the processes of fibrosis, inflammatory response, and neurotransmission (Molecules 2023, 28, 861).

[0004] sGC modulators and sGC agonists are a class of drugs that can stimulate cGMP formation, and provide tools for studying the regulatory mechanisms of sGC and its role in pathological mechanisms. The development of sGC modulators or agonists has made it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs (Molecules 2023, 28, 861). Riociguat is the first approved sGC agonist. In 2013, Riociguat was approved for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH) (J. Med. Chem. 2017, 60, 5146-5161). In the 12-week, multicentre, double-blind, randomised, placebo-controlled, pivotal PATENT-1 study, the most common AEs (occurring in ≥ 3% of patients) that were reported more frequently in the riociguat group than in the placebo group were headache (27% vs. 18%), dyspepsia / gastritis (21% vs. 8%), dizziness (20% vs. 13%), nausea (14% vs. 11%), diarrhoea (12% vs. 8%), hypotension (10% vs. 4%), vomiting (10% vs. 7%), anaemia (7% vs. 2%), gastrooesophageal reflux disease (5% vs. 2%), and constipation (5% vs. 1%). The development of novel sGC modulators or agonists to improve therapeutic effects or reduce toxic and side effects has good application prospects.Summary of the Invention

[0005] The objective of the present invention is to provide a compound having a novel structure and represented by general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating sGC-related diseases.

[0006] The compounds of the present invention have good stimulatory effects on cGMP production in LNCap cells and exhibit excellent lung pharmacokinetic properties, e.g., superior lung AUC and / or lung-to-plasma ratios compared to control 1, thereby conferring the advantages of lung targeting and reduced systemic side effects.

[0007] The present invention provides a compound represented by general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II), in some embodiments, the compound represented by general formula (I) or (II) is a compound represented by general formula (III-1) or (III-2), in some embodiments, R is selected from in some embodiments, R is selected from in some embodiments, Z is selected from CH or N; in some embodiments, Z 1 or Z 2 is each independently selected from CH or N, and at least one of Z 1 and Z 2 is N; in some embodiments, X 1 or X 2 is each independently selected from O or S; in some embodiments, A is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl; in some embodiments, A is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; in some embodiments, A is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; in some embodiments, A is selected from the following groups optionally substituted with 1 to 4 R a< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, A is selected from the following groups optionally substituted with 1 to 4 R a< : phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R 1< is -M-(CR 1a< R 1b< ) r -(CR 1c< R 1d< ) s -COOH; in some embodiments, R 1< is selected from in some embodiments, M is selected from a bond, C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, or the following groups optionally substituted with 1 to 4 R m< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R 2< is selected from C 1-6 alkyl or C 1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 R k< ; in some embodiments, R 2< is selected from C 1-5 alkyl or C 1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 R k< ; in some embodiments, R 2< is selected from C 1-4 alkyl or C 1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 R k< ; in some embodiments, R 2< is selected from methyl, ethyl, propyl, butyl, - methylene-Q, -ethylene-Q, or -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, or propylene is optionally substituted with 1 to 6 R k< ; in some embodiments, R 2< is selected from in some embodiments, Q is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from the following groups optionally substituted with 1 to 4 R q< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , and R b3< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-11 cycloalkyl or 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form the following groups optionally substituted with 1 to 4 R k< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, or tetrahydropyranyl; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, or cyclopropyl; in some embodiments, each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3-to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy; in some embodiments, each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3-to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; in some embodiments, each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; in some embodiments, each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , methyl, ethyl, methoxy, or ethoxy; in some embodiments, a, c, r, and s are each independently selected from 0, 1, 2, 3, or 4; in some embodiments, a and c are each independently selected from 0, 1 or 2; in some embodiments, c is selected from 0, 1 or 2.

[0008] A first embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein R is selected from or Z is selected from CH or N; Z 1 or Z 2 is each independently selected from CH or N, and at least one of Z 1 and Z 2 is N; X 1 or X 2 is each independently selected from O or S; A is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl; R 1< is -M-(CR 1a< R 1b< ) r -(CR 1c< R 1d< ) s -COOH; M is selected from a bond, C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-6 alkyl or C 1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 R k< ; Q is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy; a, c, r, and s are each independently selected from 0, 1, 2, 3, or 4.

[0009] A second embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-5 alkyl or C 1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 R k< ; Q is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-11 cycloalkyl or 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; the remaining definitions are the same as those in the first embodiment of the present invention.

[0010] A third embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-4 alkyl or C 1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 R k< ; Q is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; the remaining definitions are the same as those in the first or second embodiment of the present invention.

[0011] A fourth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from the following groups optionally substituted with 1 to 4 R a< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; M is selected from a bond, or the following groups optionally substituted with 1 to 4 R m< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R 2< is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, or -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, or propylene is optionally substituted with 1 to 6 R k< ; Q is selected from the following groups optionally substituted with 1 to 4 R q< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form the following groups optionally substituted with 1 to 4 R k< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, or tetrahydropyranyl; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , methyl, ethyl, methoxy, or ethoxy; the remaining definitions are the same as those in the first, second, or third embodiment of the present invention.

[0012] A fifth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from the following groups optionally substituted with 1 to 4 R a< : phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R 1< is selected from R is selected from R 2< is selected from or R a< , R c< , and R b3< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, or cyclopropyl; c is selected from 0, 1 or 2; the remaining definitions are the same as those in the first, second, third, or fourth embodiment of the present invention.

[0013] A sixth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound represented by general formula (I) is a compound represented by general formula (II), wherein A is selected from the following groups: phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R is selected from R 2< is selected from or R a< and R c< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; a and c are each independently selected from 0, 1 or 2.

[0014] A seventh embodiment of the present invention provides the above-described compound represented by general formula (I) or (II), or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound represented by general formula (I) or (II) is a compound represented by general formula (III-1) or (III-2), wherein the remaining definitions are the same as the corresponding definitions in any one of the first to sixth embodiments of the present invention.

[0015] The present invention relates to a compound as described below or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound has a structure selected from one of those in Table E-1 below:

[0016] The present invention relates to a pharmaceutical composition comprising the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0017] The present invention relates to the use of the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the above-described pharmaceutical composition in the preparation of a drug for treating sGC-related diseases.

[0018] The present invention relates to the use of the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the above-described pharmaceutical composition in the preparation of a drug for treating cardiovascular diseases, kidney diseases or respiratory diseases, preferably pulmonary arterial hypertension, pulmonary hypertension or chronic obstructive pulmonary disease.

[0019] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and a pharmaceutically acceptable excipient. The pharmaceutical composition can be in a unit dosage form (the amount of the active pharmaceutical ingredient per unit dosage form is also referred to as the "dosage strength").

[0020] The present invention also provides a method for treating a disease in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the pharmaceutical composition according to the present invention. In some embodiments, the mammal described in the present invention comprises human.

[0021] The term "effective amount" or "therapeutically effective amount" in the present application refers to a sufficient amount of the compound disclosed in the present application that is administered to ameliorate, to some extent, one or more symptoms of a disease or condition being treated (e.g., a cardiovascular disease). In some embodiments, the outcome is the reduction and / or remission of signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" in terms of the therapeutic use is an amount of the included compound disclosed in the present application that is required to provide clinically significant reduction of the symptoms of the disease. Examples of the therapeutically effective amount include, but are not limited to 0.01-1500 mg, 0.01-1000 mg, 0.01-800 mg, 0.01-600 mg, 0.1-1500 mg, 0.1-1000 mg, 0.1-800 mg, 0.1-600 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 0.01-100 mg, 0.01-50 mg, 0.01-10 mg, 0.01-5 mg, 0.05-10 mg, 0.05-5 mg, 0.1-5 mg, 1-5 mg, 0.1-1 mg, or 0.1-5 mg; in some embodiments, the pharmaceutical composition comprises, but not limited to 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, or 300 mg of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention.

[0022] A method for treating a disease in a mammal, wherein the method comprises administering to a subject a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, wherein the therapeutically effective amount is preferably 0.01-1500 mg, and the disease is preferably a cardiovascular disease.

[0023] A method for treating a disease in a mammal, wherein the method comprises administering to a subject the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention at a daily dose of 0.01-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 0.01-1500 mg / day, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 0.01 mg / day, 0.05 mg / day, 0.1 mg / day, 0.15 mg / day, 0.2 mg / day, 0.3 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, or 800 mg / day.

[0024] The present invention relates to a kit which can comprise a composition in single-dose or multi-dose form, wherein the kit comprises the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and the amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is the same as the amount in the above-described pharmaceutical composition.

[0025] In the present invention, the amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is calculated in the form of a free base in each case.

[0026] The term "dosage strength" refers to the weight of the active pharmaceutical ingredient per unit dosage form, such as a vial or a tablet.Synthesis method I:

[0027] each R d-11< is independently selected from C 1-6 alkyl; R d-12< is selected from halogen, preferably I or Br; the definitions of the remaining groups are consistent with those in the description of the present invention; a compound of general formula (D-1-1) and a compound of general formula (D-1-2) are subjected to an addition reaction to obtain a compound of general formula (D-1-3); the compound of general formula (D-1-3) and a compound of general formula (D-1-4) are subjected to a cyclisation reaction to obtain a compound of general formula (D-1-5); the compound of general formula (D-1-5) is subjected to a hydrolysis reaction to obtain a compound of general formula (I).

[0028] Unless stated to the contrary, the terms used in the description and claims of the present application have the following meanings.

[0029] The carbon, hydrogen, oxygen, sulphur, nitrogen, F, Cl, Br and I involved in the groups and compounds of the present invention all comprise their isotopes, and the carbon, hydrogen, oxygen, sulphur or nitrogen involved in the groups and compounds of the present invention is optionally substituted with one or more of their corresponding isotopes, wherein the isotopes of carbon comprise 12< C, 13< C and 14< C, the isotopes of hydrogen comprise protium (H), deuterium (D, also known as heavy hydrogen) and tritium (T, also known as superheavy hydrogen), the isotopes of oxygen comprise 16< O, 17< O and 18< O, the isotopes of sulphur comprise 32< S, 33< S, 34< S and 36< S, the isotopes of nitrogen comprise 14< N and 15< N, the isotopes of fluorine comprise 17< F and 19< F, the isotopes of chlorine comprise 35< Cl and 37< Cl, and the isotopes of bromine comprise 79< Br and 81< Br.

[0030] "Halogen" refers to F, Cl, Br or I.

[0031] "Halogen-substituted" refers to a substitution with F, Cl, Br, or I, including but not limited to a substitution with 1 to 10 substituents selected from F, Cl, Br, or I, or a substitution with 1 to 6 substituents selected from F, Cl, Br, or I, or a substitution with 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is referred to simply as "halo".

[0032] "Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof. The definition of the "alkyl" herein is consistent with this definition. The alkyl can be monovalent, divalent, trivalent or tetravalent.

[0033] "Alkylene" refers to a substituted or unsubstituted linear or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10), and examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, etc.

[0034] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The "cycloalkyl" herein is as defined above. The cycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0035] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, or 1 to 3 heteroatoms selected from N, O or S. The selectively substituted N and S in the ring of the heterocycloalkyl can be oxidised to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom; heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring; and heterocycloalkyl can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidyl, piperidyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl or piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0036] "Alkenyl" refers to a substituted or unsubstituted linear or branched unsaturated hydrocarbon group, having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc. The definition of the alkenyl herein is consistent with this definition. The alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0037] "Alkynyl" refers to a substituted or unsubstituted linear or branched unsaturated hydrocarbon group, having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with a main chain including 2 to 10 carbon atoms, including but not limited to a main chain including 2 to 6 carbon atoms, or a main chain including 2 to 4 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc. The alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0038] "Propynyl" refers to 1-propynyl or 2-propynyl.

[0039] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0040] "Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, 4- to 12-membered bicyclic ring, or 10- to 15-membered tricyclic ring system. Carbocyclyl can be connected to an aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring is optionally a monocyclic ring, a bridged ring, or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, a benzene ring, a naphthalene ring, The "carbocyclyl" or "carbocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0041] "Heterocyclyl" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The selectively substituted N and S in the ring of the heterocyclyl can be oxidised to various oxidation states. Heterocyclyl can be connected to a heteroatom or a carbon atom; heterocyclyl can be connected to an aromatic ring or a non-aromatic ring; and heterocyclyl can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, The "heterocyclyl" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0042] "Spiro ring" or "spiro ring group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, or 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may optionally contain 1 to 5 heteroatoms selected from N, O or S(=O) n . The "spiro ring" or "spiro ring group" can be monovalent, divalent, trivalent or tetravalent.

[0043] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, wherein n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: The "fused ring" or "fused ring group" can be monovalent, divalent, trivalent or tetravalent.

[0044] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two rings sharing two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, wherein n is 0, 1 or 2). The number of ring atoms includes, but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane and adamantane. The "bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0045] "Carbospiro ring", "spiro ring carbocyclyl", "spirocarbocyclyl" or "carbospiro ring group" refers to a "spiro ring" with a ring system consisting only of carbon atoms.

[0046] "Carbo-fused ring", "fused ring carbocyclyl", "fused carbocyclyl" or "carbo-fused ring group" refers to a "fused ring" with a ring system consisting only of carbon atoms.

[0047] "Carbo-bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbo-bridged ring group" refers to a "bridged ring" with a ring system consisting only of carbon atoms.

[0048] "Mono-heterocyclic ring", "monocyclic heterocyclyl" or "mono-heterocyclyl" refers to "heterocyclyl" or "heterocyclic ring" with a monocyclic system.

[0049] "Fused-heterocyclic ring", "fused-heterocyclic ring group", "fused ring heterocyclyl" or "fused-heterocyclic ring group" refers to a "fused ring" containing a heteroatom.

[0050] "Spiro-heterocyclic ring", "spiro-heterocyclyl", "spiro ring heterocyclyl" or "spiro-heterocyclic ring group" refers to a "spiro ring" containing a heteroatom.

[0051] "Bridged-heterocyclic ring", "bridged-heterocyclyl", "bridged ring heterocyclyl" or "bridged-heterocyclic ring group" refers to a "bridged ring" containing a heteroatom.

[0052] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting examples include a benzene ring, a naphthalene ring, or and "aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of connection is on the aryl ring.

[0053] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, wherein n is 0, 1 or 2), wherein the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzoimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples include and The definition of the heteroaryl herein is consistent with this definition. The heteroaryl can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of connection is on the heteroaryl ring.

[0054] "Substitution" or "substituted" refers to a substitution with 1 or more (including, but not limited to 2, 3, 4 or 5) substituents including, but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, carboxylate, -(CH 2 ) m -C(=O)-R a< , -O-(CH 2 ) m -C(=O)-R a< , -(CH2) m -C(=O)-NR b< R c< , -(CH 2 ) m S(=O) n R a< , -(CH2) m -alkenyl-R a< , OR d< or -(CH 2 ) m -alkynyl-R a< (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl, -NR b< R c< , etc., wherein R b< and R c< are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulphonyl, or trifluoromethylsulphonyl. Alternatively, R b< and R c< can form a five- or six-membered cycloalkyl or heterocyclyl. R a< and R d< are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester group, bridged ring group, spiro ring group or bicyclic ring group.

[0055] "Containing 1 to 5 heteroatoms selected from O, S and N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N.

[0056] "Substituted with 1 to X substituents selected from ..." refers to a substitution with 1, 2, 3 ... X substituents, wherein X is any integer from 1 to 10. For example, "substituted with 1 to 4 R k< " refers to a substitution with 1, 2, 3 or 4 R k< . For example, "substituted with 1 to 5 substituents selected from ..." refers to a substitution with 1, 2, 3, 4 or 5 substituents selected from ... For example, "bridged-heterocyclic ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the bridged-heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from D or F.

[0057] An X- to Y-membered ring (3 ≤ X < Y, and Y is selected from any integer between 4 and 12) includes X, X+1-, X+2-, X+3-, X+4-,...to Y-membered rings. Rings include a heterocyclic ring, a carbocyclic ring, an aromatic ring, aryl, heteroaryl, cycloalkyl, a mono-heterocyclic ring, a fused-heterocyclic ring, a spiro-heterocyclic ring, or a bridged-heterocyclic ring. For example, a "4- to 7-membered mono-heterocyclic ring" refers to a 4-, 5-, 6- or 7-membered mono-heterocyclic ring, and a "5- to 10-membered fused-heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9- or 10-membered fused-heterocyclic ring.

[0058] The term "optional" or "optionally" refers to that the events or circumstances subsequently described may but not necessarily occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, "alkyl optionally substituted with F" means that the alkyl may but not necessarily be substituted with F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.

[0059] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention, which salt maintains the biological effectiveness and characteristics of a free acid or a free base, and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.

[0060] "Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and characteristics of a compound administered.

[0061] "Co-crystal" refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between various components. The co-crystal is a multi-component crystal, which includes both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.

[0062] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.

[0063] "Stereoisomer" refers to an isomer produced as a result of different spatial arrangement of atoms in molecules, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0064] "Tautomer" refers to a functional group isomer produced by the rapid movement of an atom in two positions in a molecule, such as keto-enol isomerisation and amide-imino alcohol isomerisation.Detailed Description of Embodiments

[0065] The technical solutions of the present invention will be described in detail by the following examples, but the scope of protection of the present invention includes but is not limited thereto.

[0066] The structures of the compounds are determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in the unit of 10 -6< (ppm). NMR is determined with NMR instruments (Bruker Avance III 400 and Bruker Avance 300); the solvent for determination is deuterated dimethylsulphoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD); and the internal standard is tetramethylsilane (TMS).

[0067] MS is determined with Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0068] HPLC is determined with Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 µM).

[0069] Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate is used as a thin layer chromatography silica plate; and the silica gel plate for the thin layer chromatography (TLC) is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4 mm-0.5 mm.

[0070] Yantai Huanghai silica gel of 200-300 mesh is generally used as a carrier in column chromatography.Example 1 :

[0071] Step 1: Preparation of 1A

[0072] Compound isobutyryl chloride (7 g, 65.67 mmol) was dissolved in THF (40 mL), and the mixture was cooled to -70°C. A solution of potassium tert-butoxide in tetrahydrofuran (72 mL, 1 N) was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min, and then 100 mL of water and 50 mL of methyl tert-butyl ether were added sequentially. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.Step 2: Preparation of 1B

[0073] Compound 1A (7.77 g, 53.89 mmol) was dissolved in THF (80 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of LDA in tetrahydrofuran (80 mL, 1 N) was slowly added dropwise. After the addition, the mixture was further stirred for 30 min, warmed to 0°C and then stirred for 10 min. The mixture was cooled to -70°C, and a solution of 3-iodobenzyl bromide (16 g, 53.89 mmol) in tetrahydrofuran (20 mL) was slowly added. After the addition, the mixture was further stirred for 1 h and naturally warmed to room temperature. The reaction was quenched with 20 mL of a saturated aqueous ammonium chloride solution. 100 mL of water and 100 mL of methyl tert-butyl ether were added, and the mixture was stirred for layer separation. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V)=0 / 100-5 / 100) to obtain compound 1B (6.3 g, yield: 32%).

[0074] 1< H NMR (400 MHz, CDCl 3 ) δ 7.56-7.51 (m, 2H), 7.14-7.09 (m, 1H), 7.02 - 6.95 (m, 1H), 2.75 (s, 2H), 1.45 (s, 9H), 1.13 (s, 6H).Step 3: Preparation of 1C

[0075] Compound 1B (5.8 g, 16.10 mmol) was dissolved in THF (20 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of isopropyl magnesium chloride-lithium chloride in tetrahydrofuran (24 mL, 1 N) was slowly added dropwise. After the addition, the mixture was warmed to 0°C, stirred for 10 min and then cooled to -70°C. Diethyl oxalate (3.53 g, 24.15 mmol) was slowly added dropwise. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min. The reaction was quenched with 10 mL of a saturated aqueous ammonium chloride solution and extracted with 50 mL of methyl tert-butyl ether and 50 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-8 / 100) to obtain compound 1C (4.2 g, yield: 78%).Step 4: Preparation of 1D

[0076] Compound 1C (2.4 g, 7.18 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and water (1 mL). Malononitrile (1.90 g, 28.79 mmol) and β-alanine (0.064 g, 0.72 mmol) were added sequentially, and the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 1D (2.56 g, yield: 93%).Step 5: Preparation of 1E

[0077] Compound 1D (2.56 g, 6.69 mmol) was dissolved in THF (15 mL). Under nitrogen atmosphere, the mixture was cooled to -70°C, and a solution of methylmagnesium chloride in tetrahydrofuran (2.7 mL, 3 N) was slowly added dropwise. After the addition, the mixture was further stirred at this temperature for 10 min. The reaction was quenched with 10 ml of 1 N hydrochloric acid. 30 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 1E (2.13 g, yield: 79%).Step 6: Preparation of 1F

[0078] Compound 1E (0.54 g, 1.36 mmol), S-methylisothiourea sulphate (0.26 g, 1.36 mmol, CAS: 867-44-7) and potassium bicarbonate (0.54 g, 5.39 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 1F (0.45 g, yield: 75%).

[0079] LCMS m / z = 443.2 [M+H] +< Step 7: Preparation of 1G

[0080] Compound 1F (0.44 g, 0.99 mmol) was dissolved in THF (5 mL). m-Chloroperoxybenzoic acid (0.34 g, 1.97 mmol, wt% = 85%) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain 1G (a mixture of 1G-1 and 1G-2), which was directly used in the next step.

[0081] LCMS m / z = 457.2 [M-H] -< and LCMS m / z = 473.2 [M-H] -< Step 8: Preparation of 1H

[0082] Compound 1, 1,1,2,2-pentafluoro-4-iodobutane (2 g, 7.29 mmol), phthalimide (1.07 g, 7.29 mmol) and potassium carbonate (1.51 g, 10.94 mmol) were mixed and dissolved in DMF (20 mL). The mixture was warmed to 80°C, stirred for 3 h and cooled to room temperature. 40 mL of MTBE and 40 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 4), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 5) to obtain compound 1H (0.5 g, yield: 23%).Step 9: Preparation of 1I hydrochloride

[0083] Compound 1H (0.5 g, 1.71 mmol) was dissolved in ethanol (5 mL). Hydrazine hydrate (0.12 g, 1.98 mmol, wt% = 80%) was added, and the mixture was warmed to 78°C, stirred for 2 h and cooled to room temperature. 10 mL of ethyl acetate was added, and the mixture was filtered. The filter cake was washed with 5 mL of ethyl acetate. The filtrates were combined. A solution of hydrogen chloride in ethyl acetate (1 mL, 4 N) was added, and the mixture was concentrated under reduced pressure to obtain the hydrochloride of compound 1I, which was directly used in the next step.

[0084] LCMS m / z = 164.10 [M+H] +< Step 10: Preparation of 1J

[0085] Compound 4-chloro-2-fluoronitrobenzene (0.33 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 1J (0.43 g, yield: 72%).

[0086] LCMS m / z = 319.1 [M+H] +< Step 11: Preparation of 1K

[0087] Compound 1J (0.43 g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.64 mmol) and iron powder (0.76 g, 13.54 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 1K (0.3 g, yield: 77%).

[0088] LCMS m / z = 289.10 [M+H] +< Step 12: Preparation of 1L

[0089] Compound 1K (0.3 g, 1.04 mmol) was dissolved in DCM (5 mL), and diisopropylethylamine (0.41 g, 3.14 mmol) was added. In an ice bath, triphosgene solids (0.12 g, 0.42 mmol) were added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 1L (0.2 g, yield: 61%).

[0090] LCMS m / z = 315.0 [M+H] +< Step 13: Preparation of 1M

[0091] Compound 1L (0.2 g, 0.64 mmol), 1G (0.46 g) and potassium carbonate (0.18 g, 1.29 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 1M (55 mg, yield: 12%).

[0092] LCMS m / z = 709.70 [M+H] +< Step 14: Preparation of compound 1

[0093] Compound 1M (0.052 g, 0.073 mmol) was placed in a 50 mL single-necked flask. TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 4) to obtain compound 1 (34 mg, yield: 71%).Step 15: Compounds 1-1 and 1-2

[0094] Compound 1 (30 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: Waters 150 ap; chromatographic column: ChoralPak IC 19*250 5 um; column temperature: 35°C; mobile phase A: CO 2 , and mobile phase B: isopropanol; gradient: B 24%; back pressure: 95 bar; cycle: 3.6 min; detection wavelength: 210 nm; flow rate: 40 ml / min.

[0095] Analysis conditions: instrument: Shimadzu LC-20AD; chromatographic column: CHIRALPAK AD-H 4.6*250 mm 5 um; mobile phase A: n-hexane, and mobile phase B: ethanol; flow rate: 1 ml / min; column temperature: 35°C; detection wavelength: 210 nm; injection volume: 10 µL; run time: 20 min; isocratic elution: n-hexane: ethanol = (80 : 20).

[0096] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 1-1 (10 mg) and compound 1-2 (10 mg).Compound 1-1: retention time under analysis conditions: 5.1 min, LCMS m / z = 653.1 [M+H] +<

[0097] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, 1H), 7.53 (d, 1H), 7.28 - 7.21 (m, 1H), 7.16 - 7.03 (m, 4H), 6.78 - 6.48 (m, 2H), 4.24 (t, 2H), 2.85 - 2.65 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Compound 1-2: retention time under analysis conditions: 7.5 min, LCMS m / z = 653.1 [M+H] +<

[0098] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, 1H), 7.53 (d, 1H), 7.28 - 7.21 (m, 1H), 7.16 - 7.03 (m, 4H), 6.78 - 6.48 (m, 2H), 4.24 (t, 2H), 2.85 - 2.65 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Example 2:

[0099] Step 1: Preparation of 2A

[0100] Compound diethyl 2-(dicyanomethyl)-2-methylmalonate (CAS: 1350855-72-9) (1 g, 4.20 mmol), S-methylisothiourea sulphate (0.79 g, 4.2 mmol) and potassium bicarbonate (1.68 g, 16.78 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate was added, and the mixture was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 2A (0.9 g, yield: 76%).

[0101] LCMS m / z = 283.20 [M+H] +< Step 2: Preparation of 2B

[0102] Compound 2A (0.9 g, 3.19 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (10 mL, 7 N) was added, and the mixture was warmed to 40°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure to obtain compound 2B, which was directly used in the next step.

[0103] LCMS m / z = 254.1 [M+H] +< Step 3: Preparation of 2C

[0104] Compound 2B (0.85 g, 3.36 mmol) and Lawson's reagent (1.49 g, 3.70 mmol) were mixed and dissolved in toluene (15 mL). After the addition, the mixture was purged three times with nitrogen, warmed to 100°C and stirred overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 2C (0.52 g, yield: 57%).Step 4: Preparation of 2D

[0105] Compound methyl 4-chloro-2,2-dimethylpent-4-enoate (2 g, 11.29 mmol, CAS: 86799-85-1) was dissolved in a mixed solvent of ethanol (10 mL) and water (10 mL). In an ice bath, NBS (2.21 g, 12.42 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 1 h. The reaction was quenched by slowly adding 10 mL of a saturated aqueous sodium bicarbonate solution and extracted with 20 mL of MTBE. The organic phase was further washed with a saturated aqueous sodium bicarbonate solution (10 mL x 2), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.Step 5: Preparation of 2E

[0106] 2C (0.5 g, 1.86 mmol) and 2D (0.66 g, 2.79 mmol) were mixed and dissolved in ethanol (10 mL). The mixture was warmed to 60°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate and 20 mL of a saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred for 10 min. The organic layer was separated, washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 2E (0.55 g, yield: 73%).

[0107] LCMS m / z = 408.70 [M+H] +< Step 6: Preparation of 2F

[0108] Compound 2E (0.55 g, 1.35 mmol) was dissolved in tetrahydrofuran (5 mL), and m-chloroperoxybenzoic acid (0.47 g, 2.72 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min. 20 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain 2F (a mixture of 2F-1 and 2F-2), which was directly used in the next step.

[0109] LCMS m / z = 424.1 [M+H] +< and LCMS m / z = 440.1 [M+H] +< Step 7: Preparation of2G

[0110] Compound 1L (0.12 g, 0.38 mmol), 2F (0.19 g) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C, stirred for 16 h and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3) to obtain compound 2G (54 mg, yield: 21%).

[0111] LCMS m / z = 674.1 [M+H] +< Step 8: Preparation of compound 2

[0112] Compound 2G (0.054 g, 0.080 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.019 g, 0.79 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding 1 N hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 2 (31 mg).

[0113] LCMS m / z = 660.0 [M+H] +<

[0114] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 7.81 (d, 1H), 7.52 (d, 1H), 7.25 (s, 1H), 7.13 (dd, 1H), 7.09 - 6.96 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.81 - 2.65 (m, 2H), 1.81 (s, 3H), 1.14 - 1.04 (m, 6H).Preparation of compound 2-1 and compound 2-2:

[0115]

[0116] The trifluoroacetate of compound 2 (31 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 52 ml / min.

[0117] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution: mobile phase B: 10%-40%; time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0118] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 2-1 (10 mg) and compound 2-2 (15 mg).Compound 2-1: retention time under analysis conditions: 2.3 min, LCMS m / z = 660.0 [M+H] +< Compound 2-2: retention time under analysis conditions: 2.7 min, LCMS m / z = 660.0 [M+H] +< Example 3:

[0119] Step 1: Preparation of3A

[0120] Pyridazine (3 g, 37.50 mmol) was dissolved in chloroform (60 mL). Trifluoromethanesulphonic anhydride (12.59 g, 44.63 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. Trimethylsilyl cyanide (15.81 g, 159.26 mmol) was added, and the mixture was warmed to 60°C, reacted for 3 h and cooled. Then, N-methyl morpholine (4.93 g, 48.75 mmol) was added, and the mixture was warmed to 60°C again, reacted overnight and cooled to room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted twice with DCM. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 13) to obtain compound 3A (2.5 g, yield: 63%).

[0121] LCMS m / z = 106.20 [M+H] +< Step 2: Preparation of 3B hydrochloride

[0122] Compound 3A (2 g, 19.03 mmol) was dissolved in methanol (10 mL). 10 mL of 6 N hydrochloric acid and palladium on carbon (2.03 g, 1.90 mmol) were added, and the mixture was purged three times with hydrogen and reacted overnight under hydrogen atmosphere. The reaction solution was filtered over celite and washed 3 times with methanol. The filtrate was concentrated under reduced pressure to obtain compound 3B hydrochloride, which was directly used in the next step.Step 3: Preparation of3C

[0123] Compound 3B hydrochloride (1.1 g, 7.52 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.73 g, 9.02 mmol) were dissolved in DMF (20 mL). HATU (5.72 g, 15.04 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (2.92 g, 22.56 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 10) to obtain compound 3C (700 mg, yield: 32%).Step 4: Preparation of 3D

[0124] Compound 3C (700 mg, 2.47 mmol) was dissolved in DCE (100 mL). Phosphorus oxychloride (1.31 mL, 14.35 mmol) was added, and the mixture was warmed to reflux, reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 3D (350 mg, yield: 53%).

[0125] LCMS m / z = 266.30 [M+H] +< Step 5: Preparation of3E

[0126] Compound 3D (350 mg, 1.32 mmol) was dissolved in DCM (10 mL). NBS (246.68 mg, 1.39 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-50 / 100) to obtain compound 3E (430 mg, yield: 94%).

[0127] LCMS m / z = 344.30 [M+H] +< Step 6: Preparation of 3F

[0128] Compound 3E (400 mg, 1.16 mmol) and zinc cyanide (272.46 mg, 2.32 mmol) were added to a 50 mL single-necked flask, and then zinc powder (151.75 mg, 2.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene (385.85 mg, 0.70 mmol), tris(dibenzylidene-BASE acetone)dipalladium (318.67 mg, 0.35 mmol) and N,N-dimethylacetamide (10 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 50 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain compound 3F (320 mg, yield: 95%).

[0129] LCMS m / z = 291.1 [M+H] +< Step 7: Preparation of3G

[0130] In an ice bath, ammonium chloride (275.47 mg, 5.15 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (2.58 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 3F (300 mg, 1.03 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 3G (190 mg, yield: 60%).

[0131] LCMS m / z = 308.50 [M+H] +< Step 8: Preparation of3H

[0132] Diethyl 2-bromo-2-methylmalonate (20.00 g, 79.02 mmol) and malononitrile (5.22 g, 79.02 mmol) were dissolved in tetrahydrofuran (120 mL). In an ice bath, potassium tert-butoxide (8.87 g, 79.02 mmol) was added in portions. After the addition, the mixture was warmed to 85°C and stirred for 16 h. The reaction solution was cooled to room temperature and subjected to suction filtration to remove the solid. The filter cake was washed with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 3H (4.94 g, yield: 26%).

[0133] LCMS m / z = 239.1 [M+H] +< Step 9: Preparation of 3I

[0134] Compound 3G (190 mg, 0.62 mmol), 3H (177.25 mg, 0.74 mmol) and potassium bicarbonate (124.15 mg, 1.24 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 3I (250 mg, yield: 80%).Step 10: Preparation of 3J

[0135] Compound 3I (250 mg, 0.50 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (5 mL, 7 N) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 3J (230 mg, yield: 97%).

[0136] LCMS m / z = 471.1 [M+H] +< Step 11: Preparation of 3K

[0137] Compound 3J (230 mg, 0.49 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (237.83 mg, 0.59 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 3K (200 mg, yield: 83%).

[0138] LCMS m / z = 487.0 [M+H] +< Step 12: Preparation of3L

[0139] Compound 3K (200 mg, 0.41 mmol) was dissolved in ethanol (5 mL). 2D (145.81 mg, 0.61 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 3L (200 mg, yield: 78%).

[0140] LCMS m / z = 625.1 [M+H] +< Step 13: Preparation of compound 3

[0141] Compound 3L (200 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain compound 3 (100 mg, yield: 51%)

[0142] LCMS m / z = 611.2 [M+H] +<

[0143] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.38 - 11.89 (m, 1H), 11.33 (s, 1H), 9.00 (dd, 1H), 8.45 (dd, 1H), 7.24 (s, 1H), 6.99 (dd, 1H), 6.78 (br.s, 1H), 3.42-3.34 (m, 2H), 2.96 - 2.76 (m, 4H), 1.79 (s, 3H), 1.11 (s, 6H).Preparation of compound 3-1 and compound 3-2:

[0144]

[0145] Compound 3 (100 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 30%; c. flow rate: 54 mL / min.

[0146] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 3-1 (35 mg) and compound 3-2 (35 mg).Compound 3-1: retention time under chiral preparative conditions: 3.33 min, LCMS m / z = 611.2 [M+1] +< Compound 3-2: retention time under chiral preparative conditions: 8.60 min, LCMS m / z = 611.2 [M+1] +< Example 4:

[0147] Step 1: Preparation of 4A

[0148] Compound methyl 2-bromo-5-chlorobenzoate (2 g, 8.02 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.69 g, 8.82 mmol) were dissolved in THF (40 mL). At -78°C, sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (60 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 4A (1.6 g, yield: 54%).Step 2: Preparation of 4B

[0149] Compound 4A (1.6 g, 4.38 mmol) was dissolved in methanol (10 mL). Aminoguanidine hydrochloride (0.72 g, 6.54 mmol) and boron trifluoride diethyl etherate (1.1 mL, 8.91 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 4B, which was directly used in the next step.

[0150] LCMS m / z = 421.0 [M+H] +< Step 3: Preparation of 4C

[0151] Compound 4B (1.6 g, 3.80 mmol), 3H (1.81 g, 7.6 mmol) and potassium tert-butoxide (0.43 g, 3.8 mmol) were mixed and dissolved in tert-butanol (15 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 4C (550 mg, yield: 23%).

[0152] LCMS m / z = 613.0 [M+H] +< Step 4: Preparation of 4D

[0153] Compound 4C (550 mg, 0.90 mmol) was dissolved in DMF (10 mL). N,N-dimethylethylenediamine (119 mg, 1.35 mmol) and cuprous iodide (34.28 mg, 0.18 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 4D (170 mg, yield: 35%).

[0154] LCMS m / z = 533.30 [M+H] +< Step 5: Preparation of 4E

[0155] Compound 4D (170 mg, 0.32 mmol) was dissolved in methanol (3 mL). A solution of ammonia in methanol (3 mL, 7 M) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 4E (160 mg).

[0156] LCMS m / z = 504.1 [M+H] +< Step 6: Preparation of 4F

[0157] Compound 4E (160 mg, 0.32 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (155.32 mg, 0.38 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 4F (160 mg, yield: 96%).

[0158] LCMS m / z = 520.50 [M+H] +< Step 7: Preparation of 4G

[0159] Compound 4F (160 mg, 0.31 mmol) was dissolved in ethanol (5 mL). 2D (110.25 mg, 0.46 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 4G (110 mg, yield: 53%).Step 8: Preparation of compound 4

[0160] Compound 4G (110 mg, 0.17 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (71.33 mg, 1.7 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain the trifluoroacetate of compound 4 (90 mg).

[0161] LCMS m / z = 644.0 [M+H] +<

[0162] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.85 (d, 1H), 8.10 (d, 1H), 7.55 (dd, 1H), 7.24 (s, 1H), 7.21 - 7.01 (m, 2H), 3.37 - 3.24 (m, 2H), 2.93 (s, 2H), 2.87 - 2.70 (m, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 4-1 and compound 4-2:

[0163]

[0164] Compound 4 (90 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 25%; c. flow rate: 50 mL / min.

[0165] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 4-1 (20 mg) and compound 4-2 (20 mg).Compound 4-1: retention time under chiral preparative conditions: 3.80 min, LCMS m / z = 644.1 [M+1] +< Compound 4-2: retention time under chiral preparative conditions: 10.10 min, LCMS m / z = 644.0 [M+1] +< Example 5:

[0166]

[0167] With reference to the synthesis for Example 1 and Example 4 , the trifluoroacetate of compound 5 (15 mg) was obtained.

[0168] LCMS m / z = 604.3[M+H] +<

[0169] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 9.19 (dd, 1H), 8.67 (dd, 1H), 7.58 (dd, 1H), 7.25 (t, 1H), 7.19 - 7.03 (m, 3H), 6.99 - 6.39 (m, 2H), 3.44 - 3.33 (m, 2H), 3.01 - 2.84 (m, 2H), 2.84 - 2.69 (m, 2H), 1.79 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H).Example 6:

[0170] Step 1: Preparation of 6A

[0171] 5-Chloro-2-bromo-3-nitropyridine (5.00 g, 21.08 mmol) and tert-butyl cyanoacetate (4.32 g, 30.57 mmol) were dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (7.87 g, 56.92 mmol) was added. After the addition, the mixture was warmed to 100°C and stirred for 1 h. The reaction solution was cooled to room temperature, and water was added to dissolve potassium carbonate. Then, the mixture was adjusted to pH = 2 with dilute hydrochloric acid, with light-yellow solids precipitated. The resulting mixture was subjected to suction filtration. The filter cake was washed 3 times with water, redissolved in dichloromethane, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 6A (3.04 g, yield: 48%).Step 2: Preparation of 6B

[0172] In a 100 mL reaction flask, 26 mL of concentrated hydrochloric acid was added to 20 mL of water. 6A (3.04 g, 10.21 mmol) was added, forming a suspension. Then, glacial acetic acid (24 mL) was added. After the addition, the mixture was warmed to 80°C and stirred for 30 min. The reaction solution was cooled to room temperature. The reaction was quenched with water. 500 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic phase was washed 3 times with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 6B (1.4 g, yield: 69%).

[0173] LCMS m / z = 198.1[M+H] +< Step 3: Preparation of 6C

[0174] Compound 6B (1.20 g, 6.07 mmol) was dissolved in tetrahydrofuran (30 mL). Zinc powder (1.99 g, 30.35 mmol) was added, and then an aqueous ammonium chloride solution (1.62 g, 30.35 mmol, 5 mL) was added dropwise. At room temperature, the mixture was stirred and reacted for 0.5 h. To the reaction solution was added 1 mL of aqueous ammonia and 10 mL of water. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 6C (0.91 g, yield: 89%).

[0175] LCMS m / z = 168.1 [M+H] +< Step 4: Preparation of 6D

[0176] Compound 6C (0.61 g, 3.64 mmol) was dissolved in concentrated hydrochloric acid (3 mL) and water (15 mL). In an ice bath, sodium nitrite (0.41 g, 5.93 mmol) was added, and the mixture was stirred at room temperature for 16 h, with yellow solids precipitated. The resulting mixture was subjected to suction filtration to obtain solids, which were dissolved in glacial acetic acid (6 mL). The mixture was warmed to 100°C, reacted for 2 h and concentrated under reduced pressure. The residue was directly purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 6D (0.24 g, yield: 37%).

[0177] LCMS m / z = 179.10 [M+H] +< Step 5: Preparation of 6E

[0178] Compound 6D (0.34 g, 1.89 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (1.14 g, 4.16 mmol) were dissolved in acetonitrile (15 mL). Potassium carbonate (1.31 g, 9.45 mmol) was added. The mixture was warmed to 100°C, stirred and reacted for 16 h. The reaction solution was cooled to room temperature and subjected to suction filtration to remove solids. The filter cake was washed 3 times with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 5 / 1) to obtain compound 6E (0.44 g, yield: 71%).

[0179] LCMS m / z = 325.00 [M+H] +< Step 6: Preparation of 6F

[0180] In an ice bath, ammonium chloride (0.36 g, 6.80 mmol) was added to a 500 mL single-necked flask. Toluene (30 mL) was added, and then trimethylaluminium (3.9 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 6E (0.44 g, 1.36 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred for 6 h and cooled to room temperature. In an ice bath, silica gel and 100 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 6F (0.46 g, yield: 99%).

[0181] LCMS m / z = 342.0 [M+H] +< Step 7: Preparation of compound 6F-0

[0182] At -78°C, lithium diisopropylamide (60 mL, 2 M in THF) was added dropwise to a solution of methyl isobutyrate (10.18 g, 99.72 mmol) in tetrahydrofuran (500 mL). At -78°C, the mixture was stirred for 0.5 h, and then 3-iodobenzyl bromide (29.6 g, 99.69 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (400 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 10) to obtain compound 6F-0 (18 g, yield: 57%).

[0183] 1< H NMR (400 MHz, CDCl 3 ) δ 7.57 - 7.44 (m, 2H), 7.10 - 7.03 (m, 1H), 6.99 (t, 1H), 3.66 (s, 3H), 2.78 (s, 2H), 1.18 (s, 6H).Step 8: Preparation of compound 6F-1

[0184] At -78°C, an isopropyl magnesium chloride-lithium chloride complex (35 mL, 1.3 M in THF) was added dropwise to a solution of compound 6F-0 (10 g, 31.4 mmol) in tetrahydrofuran (200 mL), the mixture was stirred for 30 min, and then ethyl 3,3-dicyano-2-methylacrylate (synthesised with reference to synthesis, 1974: 9,669) (5.16 g, 31.43 mmol) was slowly added. After the addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL×2). The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 10) to obtain compound 6F-1 (5 g, yield: 45%).Step 9: Preparation of 6G

[0185] Compound 6F (0.10 g, 0.29 mmol), 6F-1 (0.10 g, 0.29 mmol) and potassium bicarbonate (0.09 g, 0.87 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 6G (0.16 g).

[0186] LCMS m / z = 652.2 [M+H] +< Step 10: Preparation of compound 6

[0187] Compound 6G (0.16 g, 0.25 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.10 g, 2.50 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 6 (0.14 g, yield: 87%).

[0188] LCMS m / z = 638.1 [M+H] +<

[0189] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.68 - 8.57 (m, 2H), 7.25 (t, 1H), 7.16 - 7.04 (m, 3H), 6.46 (s, 2H), 4.86 (t, 2H), 3.05 - 2.88 (m, 2H), 2.84 - 2.70 (m, 2H), 1.79 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Preparation of compound 6-1 and compound 6-2:

[0190]

[0191] Compound 6 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm*250 mm); The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 , and mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 30%; c. flow rate: 54 ml / min.

[0192] Analytical method: 1. instrument: UPC2; chromatographic column: IG (3 mm×50 mm); 2. the sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); b. gradient elution, mobile phase B: 10%-40%, time: 5 min; c. flow rate: 1.5 ml / min.

[0193] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 6-1 (55 mg) and compound 6-2 (40 mg).Compound 6-1: retention time under analysis conditions: 2.824 min, LCMS m / z = 638.1 [M+H] +< Compound 6-2: retention time under analysis conditions: 4.098 min, LCMS m / z = 638.1 [M+H] +< Example 7:

[0194]

[0195] With reference to the synthesis for Example 6, compound 7 (0.073 g) was obtained.

[0196] LCMS m / z = 622.2 [M+H] +<

[0197] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.12 (s, 1H), 9.20 (d, 1H), 8.28 (d, 1H), 7.33 - 7.20 (m, 1H), 7.14 - 7.03 (m, 3H), 6.52 - 6.30 (m, 2H), 5.00 (t, 2H), 3.10 - 2.93 (m, 2H), 2.86 - 2.68 (m, 2H), 1.80 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Example 8:

[0198] Step 1: Preparation of 8A

[0199] Compound 21D (0.5 g, 1.44 mmol), S-methylisothiourea sulphate (0.27 g, 1.44 mmol) and potassium bicarbonate (0.58 g, 5.76 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was slurried with 15 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 4) to obtain compound 8A (0.4 g).

[0200] LCMS m / z = 392.1 [M+H] +< Step 2: Preparation of8B

[0201] Compound 8A (0.52 g, 1.33 mmol) was dissolved in THF (5 mL), and m-chloroperoxybenzoic acid (0.46 g, 2.66 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain compound 8B, which was directly used in the next step.Step 3: Preparation of8C

[0202] Compound 1L (0.12 g, 0.38 mmol), 8B (0.23 g, 0.57 mmol) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 8C (54 mg, yield: 21%).

[0203] LCMS m / z = 658.2 [M+H] +< Step 4: Preparation of compound 8

[0204] Compound 8C (0.054 g, 0.082 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.020 g, 0.83 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous hydrochloric acid solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 8 (30 mg, yield: 56%).

[0205] LCMS m / z = 644.2 [M+H] +<

[0206] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 7.80 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.15-7.10 (m, 1H), 6.91-6.67 (m, 2H), 4.23 (t, 2H), 2.83 - 2.62 (m, 4H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 9:

[0207] Step 1: Preparation of9A

[0208] Compound 1I hydrochloride (0.5 g, 2.51 mmol) and 2-fluoro-3-nitropyridine (0.36 g, 2.51 mmol) were dissolved in DMSO (5 mL). DIPEA (0.97 g, 7.53 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 9A (0.62 g, yield: 86%).

[0209] LCMS m / z = 286.30 [M+H] +< Step 2: Preparation of9B

[0210] Compound 9A (0.62 g, 2.17 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.16 g, 21.69 mmol) and iron powder (1.21 g, 21.66 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 9B (0.48 g, yield: 86%).Step 3: Preparation of9C

[0211] Compound 9B (0.48 g, 1.88 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.46 g, 2.84 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 9C (0.32 g, yield: 60%).

[0212] LCMS m / z = 282.1[M+H] +< Step 4: Preparation of9D

[0213] Compound 9C (0.12 g, 0.43 mmol), 1G (0.30 g) and potassium carbonate (0.12 g, 0.87 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 9D (0.2 g, yield: 68%).

[0214] LCMS m / z = 676.3 [M+H] +< Step 5: Preparation of compound 9

[0215] Compound 9D (0.20 g, 0.30 mmol) was placed in a 50 mL single-necked flask. Trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 5). The resulting crude was further purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 9 (80 mg, yield: 43%).

[0216] LCMS m / z = 620.3[M+H] +<

[0217] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.90 (m, 1H), 11.22 (s, 1H), 8.29-8.23 (m, 1H), 8.15-8.09 (m, 1H), 7.28-7.21 (m, 1H), 7.18 - 7.03 (m, 4H), 6.80-6.44 (m, 2H), 4.25 (t, 2H), 2.92 - 2.70 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Preparation of compound 9-1 and compound 9-2:

[0218]

[0219] Compound 9 (80 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 25%; flow rate: 44 ml / min.

[0220] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0221] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 9-1 (25 mg) and compound 9-2 (35 mg).Compound 9-1: retention time under analysis conditions: 1.9 min, LCMS m / z = 620.2 [M+H] +< Compound 9-2: retention time under analysis conditions: 2.2 min, LCMS m / z = 620.2 [M+H] +< Example 10:

[0222]

[0223] With reference to the synthesis for Example 9 and Example 2, the trifluoroacetate of compound 10 (15 mg) was obtained.

[0224] LCMS m / z = 627.2 [M+H] +<

[0225] 1< H NMR (400 MHz, DMSO-d 6 ) 11.57 (s, 1H), 8.28-8.22 (m, 1H), 8.15-8.09 (m, 1H), 7.26 (s, 1H), 7.18-7.12 (m, 1H), 7.12-7.02 (m, 2H), 4.24 (t, 2H), 2.93 (s, 2H), 2.89-2.73 (m, 2H), 1.81 (s, 3H), 1.14-1.05(m, 6H).Example 11:

[0226] Step 1: Preparation of 11A

[0227] Compound 1I hydrochloride (0.5 g, 2.51 mmol) and 2,4-difluoronitrobenzene (0.40 g, 2.51 mmol) were dissolved in DMSO (5 mL). DIPEA (0.98 g, 7.58 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 11A (0.62 g, yield: 82%).Step 2: Preparation of 11B

[0228] Compound 11A (0.62 g, 2.05 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.10 g, 20.56 mmol) and iron powder (1.14 g, 20.42 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 11B (0.48 g, yield: 86%).

[0229] LCMS m / z = 273.30 [M+H] +< Step 3: Preparation of 11C

[0230] Compound 11B (0.48 g, 1.76 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.43 g, 2.66 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 11C (0.3 g, yield: 57%).

[0231] LCMS m / z = 299.1 [M+H] +< Step 4: Preparation of 11D

[0232] Compound 11C (0.14 g, 0.47 mmol), 8B (0.29 g, 0.70 mmol) and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 11D (0.07 g, yield: 23%).

[0233] LCMS m / z = 642.3 [M+H] +< Step 5: Preparation of compound 11

[0234] Compound 11D (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.026 g, 1.09 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 11 (20 mg, yield: 29%).

[0235] LCMS m / z = 628.2 [M+H] +<

[0236] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.49 (s, 1H), 7.87-7.79 (m, 1H), 7.75 (s, 1H), 7.39-7.30 (m, 1H), 6.98-6.87 (m, 1H), 6.87-6.60 (m, 2H), 4.22 (t, 2H), 2.80 - 2.60 (m, 4H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 12:

[0237] Step 1: Preparation of 12A

[0238] Compound 2-chloro-3-nitro-5-fluoropyridine (0.33 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 12A (0.42 g, yield: 74%).Step 2: Preparation of 12B

[0239] Compound 12A (0.4 g, 1.32 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 12B (0.3 g, yield: 83%).Step 3: Preparation of 12C

[0240] Compound 12B (0.3 g, 1.1 mmol) was dissolved in THF (5 mL). In an ice bath, N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 12C (0.2 g, yield: 61%).

[0241] LCMS m / z = 300.1[M+H] +< Step 4: Preparation of 12D

[0242] Compound 2E (0.3 g, 0.74 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.8 mL). Lithium hydroxide hydrate (0.17 g, 7.16 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 12D (0.25 g, yield: 86%).Step 5: Preparation of 12E

[0243] Compound 12D (0.25 g, 0.64 mmol) was dissolved in tetrahydrofuran (7 mL), and m-chloroperoxybenzoic acid (0.33 g, 1.92 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min. 20 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain compound 12E, which was directly used in the next step.Step 6: Preparation of compound 12

[0244] Compound 12C (0.05 g, 0.17 mmol), 12E (0.072 g, 0.17 mmol) and potassium carbonate (0.047 g, 0.34 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 12 (10 mg, yield: 9%).

[0245] LCMS m / z = 645.2[M+H] +<

[0246] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.35 (dd, 1H), 8.17 - 8.13 (m, 1H), 7.26 (s, 1H), 7.22-7.02 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.72 (m, 2H), 1.81 (s, 3H), 1.16-1.04 (m, 6H).Preparation of compound 12-1 and compound 12-2:

[0247]

[0248] Compound 12 (110 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 12%; c. flow rate: 40 ml / min.

[0249] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 12-1 (50 mg) and compound 12-2 (50 mg).Compound 12-1: retention time under chiral preparative conditions: 9.62 min, LCMS m / z = 645.2 [M+H] +<

[0250] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.35 (dd, 1H), 8.18 - 8.10 (m, 1H), 7.26 (s, 1H), 7.23 - 7.01 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.71 (m, 2H), 1.80 (s, 3H), 1.16 - 1.03 (m, 6H).Compound 12-2: retention time under chiral preparative conditions: 13.68 min, LCMS m / z = 645.2 [M+H] +<

[0251] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 8.35 (dd, 1H), 8.19 - 8.12 (m, 1H), 7.26 (s, 1H), 7.22 - 7.05 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.71 (m, 2H), 1.81 (s, 3H), 1.16 - 1.02 (m, 6H).Example 13:

[0252] Step 1: Preparation of 13B

[0253] Compound 2-chloro-3-nitro-5-fluoropyridine (0.3 g, 1.87 mmol) and compound 13A (0.21 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 13B (0.4 g, yield: 84%).Step 2: Preparation of 13C

[0254] Compound 13B (0.4 g, 1.58 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.64 mmol) and iron powder (0.76 g, 13.54 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 13C (0.3 g, yield: 85%).Step 3: Preparation of 13D

[0255] Compound 13C (0.3 g, 1.34 mmol) was dissolved in THF (15 mL). In an ice bath, N,N'-carbonyldiimidazole (0.65 g, 4.01 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 13D (0.24 g, yield: 72%).

[0256] LCMS m / z = 250.2[M+H] +< Step 4: Preparation of compound 13

[0257] Compound 13D (40 mg, 0.16 mmol), 12E (68 mg, 0.16 mmol) and potassium carbonate (44 mg, 0.32 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 13 (20 mg, yield: 21%).

[0258] LCMS m / z = 595.3[M+H] +<

[0259] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.28 (dd, 1H), 8.13 - 8.07 (m, 1H), 7.26 (s, 1H), 7.22-7.01 (m, 2H), 3.74 (d, 2H), 2.93 (s, 2H), 1.97- 1.86 (m, 1H), 1.81 (s, 3H), 1.74 - 1.52 (m, 5H), 1.26 - 0.92 (m, 11H).Example 14:

[0260] Step 1: Preparation of 14A

[0261] Compound 2,3-difluoronitrobenzene (0.3 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 14A (0.4 g, yield: 71%).Step 2: Preparation of 14B

[0262] Compound 14A (0.4 g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.7 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 14B (0.3 g, yield: 84%).Step 3: Preparation of 14C

[0263] Compound 14B (0.3 g, 1.1 mmol) was dissolved in THF (10 mL). In an ice bath, N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 14C (0.2 g, yield: 61%).

[0264] LCMS m / z = 299.1[M+H] +< Step 4: Preparation of 14D

[0265] Compound 14C (0.1 g, 0.34 mmol), 2F (0.15 g) and potassium carbonate (0.094 g, 0.68 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 14D (20 mg, yield: 9%).Step 5: Preparation of trifluoroacetate of compound 14

[0266] Compound 14D (20 mg, 0.03 mmol) was dissolved in a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL). Lithium hydroxide hydrate (12.6 mg, 0.3 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain the trifluoroacetate of compound 14 (10 mg)

[0267] LCMS m / z = 644.2[M+H] +<

[0268] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 7.64-7.56 (m, 1H), 7.26 (s, 1H), 7.14-7.04 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.82-2.62 (m, 2H), 1.82 (s, 3H), 1.15-1.05 (m, 6H).Preparation of compound 14-1 and compound 14-2

[0269] Compound 14 (100 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 20%; c. flow rate: 40 ml / min.

[0270] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 14-1 (40 mg) and compound 14-2 (40 mg). Compound 14-1: retention time under chiral preparative conditions: 5.40 min, LCMS m / z = 644.2 [M+H] +<

[0271] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 7.64 - 7.56 (m, 1H), 7.26 (s, 1H), 7.16 - 6.99 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.81-2.64 (m, 2H), 1.82 (s, 3H), 1.15 - 1.05 (m, 6H).Compound 14-2: retention time under chiral preparative conditions: 8.53 min, LCMS m / z = 644.2 [M+H] +<

[0272] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 7.64 - 7.55 (m, 1H), 7.26 (s, 1H), 7.20 - 6.95 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.82 - 2.62 (m, 2H), 1.82 (s, 3H), 1.18 - 1.01 (m, 6H).Example 15:

[0273] Step 1: Preparation of 15A

[0274] Compound 2,3-difluoronitrobenzene (0.23 g, 1.87 mmol) and compound 15A (0.3 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.71 g, 5.49 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 15B (0.4 g, yield: 81%).Step 2: Preparation of 15C

[0275] Compound 15B (0.4 g, 1.51 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.81 g, 15.1 mmol) and iron powder (0.84 g, 15.1 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 15C (0.3 g, yield: 85%).Step 3: Preparation of 15D

[0276] Compound 15C (0.3 g, 1.28 mmol) was dissolved in THF (10 mL). In an ice bath, N,N'-carbonyldiimidazole (0.62 g, 3.84 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 15D (0.2 g, yield: 60%).

[0277] LCMS m / z = 261.2[M+H] +< Step 4: Preparation of 15E

[0278] Compound 15D (0.15 g, 0.58 mmol), 2F (0.25 g) and potassium carbonate (0.16 g, 1.16 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 15E (0.1 g, yield: 28%).Step 5: Preparation of compound 15

[0279] Compound 15E (100 mg, 0.16 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL). Lithium hydroxide hydrate (38 mg, 1.6 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain the trifluoroacetate of compound 15 (20 mg)

[0280] LCMS m / z = 606.2[M+H] +<

[0281] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 7.61 (d, 1H), 7.40-7.31 (m, 1H), 7.29 - 6.91 (m, 8H), 5.23 (s, 2H), 2.93 (s, 2H), 1.82 (s, 3H), 1.10 (s, 6H).Preparation of compound 15-1 and compound 15-2:

[0282] Compound 15 (200 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0283] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 15-1 (70 mg) and compound 15-2 (80 mg).Compound 15-1: retention time under chiral preparative conditions: 7.38 min, LCMS m / z = 606.2 [M+1] +< Compound 15-2: retention time under chiral preparative conditions: 11.93 min, LCMS m / z = 606.2 [M+1] +< Example 16:

[0284]

[0285] With reference to the synthesis for Example 8, compound 16 (20 mg) was obtained.

[0286] LCMS m / z = 628.2[M+H] +<

[0287] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 7.75 (s, 1H), 7.63 - 7.56 (m, 1H), 7.13-7.05 (m, 2H), 6.96-6.68 (m, 2H), 4.29 (t, 2H), 2.82 - 2.60 (m, 4H), 1.82 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H).Example 17:

[0288] Step 1: Preparation of 17A

[0289] Compound methyl 2-bromo-5-fluorobenzoate (5 g, 21.43 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (5.66 g, 23.57 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (32.1 mL, 2 M, 64.28 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (160 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 17A (2.9 g, yield: 38%).Step 2: Preparation of 17B

[0290] Compound 17A (2 g, 5.73 mmol) was dissolved in methanol (20 mL). Aminoguanidine hydrochloride (0.95 g, 8.59 mmol) and boron trifluoride diethyl etherate (1.41 mL, 11.46 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 17B, which was directly used in the next step.

[0291] LCMS m / z = 405.10 [M+H] +< Step 3: Preparation of 17C

[0292] Compound 17B (1 g, 2.47 mmol), 3H (1.18 g, 4.94 mmol) and potassium tert-butoxide (0.28 g, 2.47 mmol) were mixed and dissolved in tert-butanol (10 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 17C (320 mg, yield: 21%).Step 4: Preparation of 17D

[0293] Compound 17C (300 mg, 0.50 mmol) was dissolved in DMF (5 mL). N,N-dimethylethylenediamine (66.11 mg, 0.75 mmol) and cuprous iodide (19.04 mg, 0.10 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 17D (190 mg, yield: 73%).Step 5: Preparation of 17E

[0294] Compound 17D (190 mg, 0.37 mmol) was dissolved in methanol (3 mL). A solution of ammonia in methanol (3 mL, 7 M) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 17E (180 mg).

[0295] LCMS m / z = 488.30 [M+H] +< Step 6: Preparation of 17F

[0296] Compound 17E (180 mg, 0.37 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (224.48 mg, 0.55 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 17F (170 mg, yield: 91%).

[0297] LCMS m / z = 504.20 [M+H] +< Step 7: Preparation of17G

[0298] Compound 17F (170 mg, 0.34 mmol) was dissolved in ethanol (5 mL). 2D (110.25 mg, 0.46 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 17G (150 mg, yield: 68%).

[0299] LCMS m / z = 642.40 [M+H] +< Step 8: Preparation of compound 17

[0300] Compound 17G (150 mg, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (96.51 mg, 2.3 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude was further subjected to preparative HPLC (instrument: Waters AutoP (preparative liquid phase); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm); composition of mobile phase: Mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonium acetate) to obtain compound 17 (65 mg, yield: 45%).

[0301] LCMS m / z = 628.20 [M+H] +<

[0302] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.26-12.02 (m, 1H), 11.52 (s, 1H), 8.87 (dd,1H), 7.81 (dd, 1H), 7.47-7.39 (m, 1H), 7.25 (s, 1H), 7.20-7.00 (m, 2H), 3.30 - 3.24 (m, 2H), 2.93 (s, 2H), 2.88 - 2.66 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 17-1 and compound 17-2:

[0303] Compound 17 (60 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 30%; c. flow rate: 45 mL / min.

[0304] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 17-1 (15 mg) and compound 17-2 (20 mg). Compound 17-1: retention time under chiral preparative conditions: 3.33 min, LCMS m / z = 628.0 [M+1] +<

[0305] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.24 - 12.11 (m, 1H), 11.52 (s, 1H), 8.87 (dd, 1H), 7.81 (dd, 1H), 7.49 - 7.38 (m, 1H), 7.25 (s, 1H), 7.21 - 7.01 (m, 2H), 3.30 - 3.24 (m, 2H), 2.93 (s, 2H), 2.87 - 2.69 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Compound 17-2: retention time under chiral preparative conditions: 7.02 min, LCMS m / z = 628.0 [M+1] +< Example 18:

[0306]

[0307] With reference to the synthesis for Example 3 and Example 6, compound 18 (100 mg) was obtained.

[0308] LCMS m / z = 604.2 [M+H] +<

[0309] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.55-11.75 (m, 1H), 11.14 (s, 1H), 8.97 (d, 1H), 8.50 (s, 1H), 7.28-7.21 (m, 1H), 7.18 - 7.00 (m, 4H), 6.72-6.35 (m, 2H), 3.46 - 3.35 (m, 2H), 2.95-2.69 (m, 4H), 1.79 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H).Example 19:

[0310] Step 1: Preparation of 19A

[0311] Compound 3B hydrochloride (2.83 g, 19.41 mmol) and o-fluorophenylacetic acid (2 g, 12.94 mmol) were dissolved in DMF (20 mL). HATU (7.38 g, 19.41 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (5.02 g, 38.81 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 10) to obtain compound 19A (420 mg, yield: 13%).

[0312] LCMS m / z = 246.2 [M+H] +< Step 2: Preparation of 19B

[0313] Compound 19A (420 mg, 1.71 mmol) was dissolved in DCE (20 mL). Phosphorus oxychloride (0.91 mL, 9.94 mmol) was added, and the mixture was warmed to reflux, reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 19B (250 mg, yield: 64%).

[0314] LCMS m / z = 228.1 [M+H] +< Step 3: Preparation of 19C

[0315] Compound 19B (250 mg, 1.10 mmol) was dissolved in DCM (10 mL). NBS (215.36 mg, 1.21 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-50 / 100) to obtain compound 19C (280 mg, yield: 83%).

[0316] LCMS m / z = 305.90 [M+H] +< Step 4: Preparation of 19D

[0317] Compound 19C (280 mg, 0.91 mmol) and zinc cyanide (220 mg, 2.06 mmol) were added to a 50 mL single-necked flask, and then zinc powder (150 mg, 2.29 mmol), 1,1'-bis(diphenylphosphino)ferrocene (302.69 mg, 0.55 mmol), tris(dibenzylidene-BASE acetone)dipalladium (250 mg, 0.27 mmol) and N,N-dimethylacetamide (10 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 50 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain compound 19D (210 mg, yield: 91%).

[0318] LCMS m / z = 253.10 [M+H] +< Step 5: Preparation of 19E

[0319] In an ice bath, ammonium chloride (221.98 mg, 4.15 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (2.07 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 19D (210 mg, 0.83 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 19E (200 mg, yield: 89%).

[0320] LCMS m / z = 270.2 [M+H] +< Step 6: Preparation of 19F

[0321] Compound 19E (100 mg, 0.37 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (201.70 mg, 0.55 mmol) and potassium bicarbonate (111.13 mg, 1.11 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 19F (190 mg, yield: 87%).

[0322] LCMS m / z = 587.2 [M+H] +< Step 7: Preparation of compound 19

[0323] Compound 19F (190 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain the trifluoroacetate of compound 19 (160 mg).

[0324] LCMS m / z = 573.1 [M+H] +<

[0325] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.41 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.36 - 7.10 (m, 5H), 7.04 (dd, 1H), 6.98-6.79 (m, 2H), 4.51 (s, 2H), 2.93 (s, 2H), 1.79 (s, 3H), 1.10 (s, 6H).Preparation of compound 19-1 and compound 19-2:

[0326] Compound 19 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: Waters 150 Prep-SFC; chromatographic column: AD; column temperature: 35°C; mobile phase A: CO 2 , and mobile phase B: methanol / acetonitrile (aqueous ammonia 0.1%); gradient: B: 55%; back pressure: 100 bar; cycle: 5.3 min; detection wavelength: 220 nm; flow rate: 100 ml / min.

[0327] Analysis conditions: instrument: SHIMADZU LC-30AD sf; chromatographic column: AD; mobile phase A: CO 2 , and mobile phase B: methanol and acetonitrile (0.05% DEA); flow rate: 3 ml / min; column temperature: 35°C; detection wavelength: 220 nm.

[0328] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 19-1 (56 mg) and compound 19-2 (61 mg). Compound 19-1: retention time under analysis conditions: 0.519 min, LCMS m / z = 573.2 [M+H] +<

[0329] 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.96 - 9.69 (m, 1H), 9.00 (dd, 1H), 8.43 (dd, 1H), 7.38 - 7.06 (m, 5H), 6.98 (dd, 1H), 6.89 - 6.70 (m, 2H), 4.49 (s, 2H), 2.93 (s, 2H), 1.78 (s, 3H), 1.09 (s, 6H).Compound 19-2: retention time under analysis conditions: 1.553 min, LCMS m / z = 573.1 [M+H] +<

[0330] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.85 - 11.05 (m, 1H), 9.00 (dd, 1H), 8.43 (dd, 1H), 7.37 - 7.09 (m, 5H), 6.98 (dd, 1H), 6.87 - 6.71 (m, 2H), 4.49 (s, 2H), 2.93 (s, 2H), 1.78 (s, 3H), 1.09 (s, 6H).Example 20:

[0331]

[0332] With reference to the synthesis for Example 6 and Example 21, compound 20 (0.035 g) was obtained.

[0333] LCMS m / z = 645.1 [M+H] +<

[0334] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.55 (s, 1H), 8.66-8.61 (m, 2H), 7.26 (s, 1H), 6.90 (br.s, 2H), 4.86 (t, 2H), 3.04 - 2.86 (m, 4H), 1.81 (s, 3H), 1.10 (s, 6H).Example 21:

[0335] Step 1: Preparation of 21A

[0336] Ethyl 2-cyanopropionate (5.00 g, 39.32 mmol) was added to a 100 mL reaction flask. In an ice bath, trimethylchlorosilane (8.54 g, 78.64 mmol) was added dropwise, and then water (1.42 g, 78.64 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 4 h. 50 mL of water was added to the reaction solution. The mixture was extracted with n-hexane, and the aqueous phase was separated, collected, basified with a saturated aqueous sodium bicarbonate solution, and extracted 3 times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain compound 21A (1.46 g, yield: 25%).

[0337] LCMS m / z = 146.1 [M+H] +< Step 2: Preparation of 21B

[0338] Compound 2D (0.50 g, 2.11 mmol) and 21A (0.31 g, 2.15 mmol) were dissolved in ethyl acetate (10 mL), and then silver trifluoromethanesulphonate (0.54 g, 2.11 mmol) was added. After the addition, the mixture was warmed to 90°C and stirred for 2 h in the dark. The reaction solution was cooled to room temperature and subjected to suction filtration to remove solids. The filter cake was washed 3 times with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21B (0.30 g, yield: 31%).

[0339] LCMS m / z = 284.40 [M+H] +< Step 3: Preparation of21C

[0340] Compound 21B (0.30 g, 1.06 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen atmosphere, lithium bis(trimethylsilyl)amide (0.59 mL, 1.17 mmol, 2 M) was added dropwise in an ice bath, and the mixture was reacted at the same temperature for 0.5 hours. Then, N-bromosuccinimide (0.21 g, 1.17 mmol) was added. After the addition, the mixture was reacted for 0.5 hours in an ice bath. The reaction was quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21C (0.217 g, yield: 56%).

[0341] LCMS m / z = 362.40 [M+H] +< Step 4: Preparation of 21D

[0342] Compound 21C (0.217 g, 0.60 mmol) and malononitrile (0.079 g, 1.20 mmol) were dissolved in tetrahydrofuran (10 mL). In an ice bath, DBU (0.18 g, 1.20 mmol) was added dropwise. After the addition, the mixture was reacted in an ice bath for 0.5 hours. The reaction was quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21D (0.16 g, yield: 76%).

[0343] LCMS m / z = 348.1 [M+H] +< Step 5: Preparation of21E

[0344] Compound 6F (0.10 g, 0.29 mmol), 21D (0.10 g, 0.29 mmol) and potassium bicarbonate (0.087 g, 0.87 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred and reacted for 16 hours, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 21E (0.142 g, yield: 76%).

[0345] LCMS m / z = 643.2[M+H] +< Step 6: Preparation of compound 21

[0346] Compound 21E (0.142 g, 0.22 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.092 g, 2.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 21 (0.095 g, yield: 67%).

[0347] LCMS m / z = 629.1 [M+H] +<

[0348] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.47 (s, 1H), 8.65-8.61 (m, 2H), 7.75 (s, 1H), 6.79 - 6.41 (m, 2H), 4.86 (t, 2H), 3.08-2.87 (m, 2H), 2.73-2.61 (m, 2H), 1.82 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 22:

[0349]

[0350] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 22 (0.031 g) was obtained.

[0351] LCMS m / z = 611.2 [M+H] +<

[0352] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 8.76 (d, 1H), 8.52 (d, 1H), 7.67-7.59 (m, 1H), 7.27 (s, 1H), 7.13-6.90 (m, 2H), 4.92 (t, 2H), 3.05 - 2.89 (m, 4H), 1.83 (s, 3H), 1.11 (s, 6H).Example 23:

[0353]

[0354] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 23 (0.021 g) was obtained.

[0355] LCMS m / z = 573.2 [M+H] +<

[0356] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.71 (d, 1H), 8.40 (d, 1H), 7.62-7.51 (m, 1H), 7.44-7.32 (m, 1H), 7.30 - 7.12 (m, 4H), 7.05-6.80 (m, 2H), 5.86 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 24:

[0357]

[0358] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 24 (0.117 g) was obtained.

[0359] LCMS m / z = 591.2 [M+H] +<

[0360] 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.00-11.60 (m, 1H), 11.53 (s, 1H), 8.70 (d, 1H), 8.39 (d, 1H), 7.63-7.51 (m, 1H), 7.46-7.35 (m, 1H), 7.26 (s, 1H), 7.23-7.13 (m, 1H), 7.08-6.98 (m, 1H), 6.98-6.82 (m, 2H), 5.91 (s, 2H), 2.94 (s, 2H), 1.82 (s, 3H), 1.10 (s, 6H).Example 25:

[0361]

[0362] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 25 (250 mg) was obtained.

[0363] LCMS m / z = 645.1 [M+H] +<

[0364] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.35-11.95 (m, 1H), 11.43 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 7.28 (s, 1H), 6.89 (br.s, 2H), 4.98 (t, 2H), 3.09 - 2.88 (m, 4H), 1.83 (s, 3H), 1.10 (s, 6H).Example 26:

[0365]

[0366] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 26 (100 mg) was obtained.

[0367] LCMS m / z = 629.1 [M+H] +<

[0368] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.16 (br.s, 1H), 11.37 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 6.73 - 6.45 (m, 2H), 4.98 (t, 2H), 3.08 - 2.91 (m, 2H), 2.75-2.61 (m, 2H), 1.84 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).Example 27:

[0369]

[0370] With reference to the synthesis for Example 16, the trifluoroacetate of compound 27 (10 mg) was obtained.

[0371] LCMS m / z = 578.3[M+H] +< Example 28:

[0372]

[0373] With reference to the synthesis for Example 15, the trifluoroacetate of compound 28 (20 mg) was obtained.

[0374] LCMS m / z = 623.5[M-H] -<

[0375] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 8.37 (dd, 1H), 8.15 - 8.05 (m, 1H), 7.44 - 7.30 (m, 1H), 7.25 (s, 1H), 7.21 - 7.00 (m, 4H), 5.18 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 29:

[0376]

[0377] With reference to the synthesis for Example 5, compound 29 (6 mg) was obtained.

[0378] LCMS m / z = 611.1[M+H] +<

[0379] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.87 - 11.06 (m, 1H), 9.17 (d, 1H), 8.67 (d, 1H), 7.56 (dd, 1H), 7.32 - 7.07 (m, 3H), 3.41 - 3.33 (m, 2H), 2.99 - 2.81 (m, 4H), 1.81 (s, 3H), 1.10 (s, 6H).Example 30:

[0380]

[0381] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 30 (170 mg) was obtained.

[0382] LCMS m / z = 629.1 [M+H] +<

[0383] 1< H NMR (400 MHz, DMSO-d 6 )δ 11.47 (s, 1H), 9.23 (s, 1H), 8.31 (s, 1H), 7.26 (s, 1H), 6.88 (s, 2H), 5.00 (t, 2H), 3.10 - 2.86 (m, 4H), 1.82 (s, 3H), 1.10 (s, 6H).Example 31:

[0384] Step 1: Preparation of31A

[0385] Compound 11C (0.14 g, 0.47 mmol), 2F (0.30 g) and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 31A (70 mg, yield: 23%).

[0386] LCMS m / z = 658.3 [M+H] +< Step 2: Preparation of compound 31

[0387] Compound 31A (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL). Lithium hydroxide (0.026 g, 1.09 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 31 (20 mg, yield: 28%).

[0388] LCMS m / z = 644.2 [M+H] +<

[0389] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 7.83 (dd, 1H), 7.35 (dd, 1H), 7.26 (s, 1H), 7.17 - 6.99 (m, 2H), 6.96 - 6.87 (m, 1H), 4.22 (t, 2H), 2.93 (s, 2H), 2.83 - 2.63 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 31-1 and compound 31-2:

[0390] Compound 31 (180 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol / isopropanol = 1 / 1 (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 25%; c. flow rate: 40 mL / min.

[0391] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 31-1 (75 mg) and compound 31-2 (80 mg). Compound 31-1: retention time under chiral preparative conditions: 4.37 min, LCMS m / z = 644.2 [M+1] +<

[0392] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 7.83 (dd, 1H), 7.35 (dd, 1H), 7.26 (s, 1H), 7.14 - 6.98 (m, 2H), 6.96 - 6.86 (m, 1H), 4.21 (t, 2H), 2.93 (s, 2H), 2.84 - 2.64 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Compound 31-2: retention time under chiral preparative conditions: 6.45 min, LCMS m / z = 644.2 [M+1] +<

[0393] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (dd, 1H), 7.35 (dd, 1H), 7.25 (s, 1H), 7.12 - 7.00 (m, 2H), 6.95 - 6.87 (m, 1H), 4.22 (t, 2H), 2.93 (s, 2H), 2.82 - 2.63 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 32:

[0394] Step 1: Preparation of 32A

[0395] Compound methyl 2-bromo-5-chlorobenzoate (5 g, 20.07 mmol) and o-fluorophenylacetic acid (3.40 g, 22.08 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (25.09 mL, 2 M, 50.17 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (150 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 32A (5.7 g, yield: 86%).

[0396] LCMS m / z = 327.0 [M+H] +< Step 2: Preparation of 32B

[0397] Compound 32A (3 g, 9.16 mmol) was dissolved in methanol (30 mL). Aminoguanidine hydrochloride (1.52 g, 13.75 mmol) and boron trifluoride diethyl etherate (2.26 mL, 18.32 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 32B, which was directly used in the next step.

[0398] LCMS m / z = 383.3 [M+H] +< Step 3: Preparation of32C

[0399] Compound 32B (600 mg, 1.56 mmol) was dissolved in DMF (10 mL). N,N-dimethylethylenediamine (206.27 mg, 2.34 mmol) and cuprous iodide (148.55 mg, 0.78 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 4 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 32C (200 mg, yield: 49%).

[0400] LCMS m / z = 261.2 [M+H] +< Step 4: Preparation of 32D

[0401] Compound 32C (60 mg, 0.23 mmol), 2F (107.15 mg) and caesium carbonate (149.88 mg, 0.46 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C, stirred for 40 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 115-111) to obtain compound 32D (60 mg, yield: 42%).

[0402] LCMS m / z = 620.2[M+H] +< Step 5: Preparation of compound 32

[0403] Compound 32D (60 mg, 0.097 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (40.70 mg, 0.97 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous hydrochloric acid solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 32 (15 mg).

[0404] LCMS m / z = 606.2[M+H] +<

[0405] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.85 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 7.39 (t, 1H), 7.35 - 7.02 (m, 6H), 4.40 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 32-1 and compound 32-2:

[0406] Compound 32 (65 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: isopropanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0407] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 32-1 (20 mg) and compound 32-2 (25 mg).Compound 32-1: retention time under chiral preparative conditions: 7.40 min, LCMS m / z = 606.0 [M+1] +< Compound 32-2: retention time under chiral preparative conditions: 11.97 min, LCMS m / z = 606.0 [M+1] +< Example 33:

[0408]

[0409] With reference to the synthesis for Example 17, the trifluoroacetate of compound 33 (15 mg) was obtained.

[0410] LCMS m / z = 612.3 [M+H] +<

[0411] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.86 (dd, 1H), 7.81 (dd, 1H), 7.75 (s, 1H), 7.47 - 7.37 (m, 1H), 7.20 - 6.46 (m, 2H), 3.35 - 3.23 (m, 2H), 2.87 - 2.72 (m, 2H), 2.71 - 2.61 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 34:

[0412]

[0413] With reference to the synthesis for Example 4, the trifluoroacetate of compound 34 (8 mg) was obtained.

[0414] LCMS m / z = 590.2 [M+H] +<

[0415] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 8.84 (d, 1H), 7.82 (d, 1H), 7.74 (s, 1H), 7.52 (dd, 1H), 7.42 - 7.27 (m, 2H), 7.24 - 7.13 (m, 2H), 7.03 - 6.65 (m, 2H), 4.40 (s, 2H), 2.71 - 2.58 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H).Example 35:

[0416] Step 1: Preparation of 35B

[0417] Compound 35A (CAS: 1361570-31-1, synthesised with reference to US 2013210824) (1 g, 3.23 mmol) was dissolved in DMSO (5 mL). Sodium chloride (0.29 g, 4.93 mmol) and water (0.5 mL) were added sequentially. The mixture was warmed to 160°C, stirred for 30 min, cooled to room temperature and extracted with 10 mL of water and 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 35B (0.7 g, yield: 86%).Step 2: Preparation of35C

[0418] Compound 35B (0.7 g, 2.79 mmol) was dissolved in ethylene glycol (7 mL). Hydrazine hydrate (1.24 g, 19.75 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 14 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 35C (0.35 g, yield: 51%).

[0419] LCMS m / z = 246.1 [M+H] +< Step 3: Preparation of35D

[0420] Compound 35C (0.1 g, 0.41 mmol), 2F (0.21 g) and potassium carbonate (0.057 g, 0.41 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 35D (0.22 g, yield: 88%).

[0421] LCMS m / z = 605.1 [M+H] +< Step 4: Preparation of compound 35

[0422] Compound 35D (0.22 g, 0.36 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.086 g, 3.59 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 35 (0.15 g, yield: 70%).

[0423] LCMS m / z = 591.2 [M+H] +<

[0424] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.55 (s, 1H), 9.04 (dd, 1H), 8.68 (d, 1H), 7.42 - 7.35 (m, 1H), 7.33 - 7.05 (m, 6H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 35-1 and compound 35-2:

[0425] Compound 35 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 54 ml / min.

[0426] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0427] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 35-1 (60 mg) and compound 35-2 (70 mg).Compound 35-1: retention time under analysis conditions: 3.4 min, LCMS m / z = 591.1 [M+H] +< Compound 35-2: retention time under analysis conditions: 5.2 min, LCMS m / z = 591.1[M+H] +< Example 36:

[0428] Step 1: Preparation of36A

[0429] Compound 2,3-difluorophenylacetic acid (1 g, 5.81 mmol) was dissolved in methanol (10 mL), and p-toluenesulphonic acid monohydrate (0.11 g, 0.58 mmol) was added. The mixture was warmed to reflux and reacted for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (10 mL×2) and a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure, and the residue was directly used in the next step.Step 2: Preparation of36B

[0430] Compound 36A (1.11 g, 5.95 mmol) was dissolved in THF (10 mL). LiHMDS (7.14 mmol, 7.14 mL, 1 N) was slowly added dropwise in a dry ice-ethanol bath. After the addition, the mixture was stirred at -70°C for 1 h. At this temperature, a solution of 3,5-difluoropicolinoyl chloride (CAS: 1048340-35-7, synthesised with reference to WO 2011158149) (1.27 g, 7.14 mmol) in THF (10 mL) was slowly added dropwise. After the addition, the mixture was naturally warmed to room temperature, and the reaction was quenched with 10 mL of a saturated aqueous ammonium chloride solution and extracted with 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36B (0.5 g, yield: 26%).Step 3: Preparation of36C

[0431] Compound 36B (0.5 g, 1.53 mmol) was dissolved in DMSO (5 mL). Sodium chloride (0.13 g, 2.29 mmol) and water (0.5 mL) were added sequentially. The mixture was warmed to 160°C, stirred for 30 min, cooled to room temperature and extracted with 10 mL of water and 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36C (0.3 g, yield: 73%).Step 4: Preparation of 36D

[0432] Compound 36C was dissolved in ethylene glycol (4 mL). Hydrazine hydrate (0.49 g, 7.86 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 8 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 36D (0.14 g, yield: 48%).

[0433] LCMS m / z = 264.3 [M+H] +< Step 5: Preparation of36E

[0434] Compound 36D (0.1 g, 0.38 mmol), 2F (0.19 g) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 36E (0.2 g, yield: 84%).

[0435] LCMS m / z = 623.2 [M+H] +< Step 6: Preparation of compound 36

[0436] Compound 36E (0.2 g, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.077 g, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 36 (0.12 g, yield: 61%).

[0437] LCMS m / z = 609.2 [M+H] +<

[0438] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.54 (s, 1H), 9.05 (dd, 1H), 8.69 (d, 1H), 7.42 - 7.02 (m, 6H), 4.49 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 36-1 and compound 36-2:

[0439] Compound 36 (100 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 54 ml / min.

[0440] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0441] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 36-1 (39 mg) and compound 36-2 (35 mg).Compound 36-1: retention time under analysis conditions: 3.3 min, LCMS m / z = 609.2 [M+H] +< Compound 36-2: retention time under analysis conditions: 5.4 min, LCMS m / z = 609.2 [M+H] +< Example 37:

[0442] Step 1: Preparation of37A

[0443] THF (10 mL) was placed in a three-necked flask. High-purity zinc powder (0.74 g, 11.31 mmol) was added. The mixture was purged three times with nitrogen, and 1,2-dibromoethane (0.11 g, 0.56 mmol) was added. After the addition, the mixture was warmed to 70°C, stirred for 10 min and cooled to room temperature. Trimethylchlorosilane (0.061 g, 0.56 mmol) was slowly added. After the addition, the mixture was stirred vigorously at room temperature for 10 min. A solution of 1,1,1,2,2-pentafluoro-4-iodobutane (1.55 g, 5.66 mmol) in THF (5 mL) was slowly added dropwise. After the addition, the mixture was further stirred at room temperature for 2 h, and the resulting reagent was set aside for subsequent use. In another reaction flask, 3,5-difluoropicolinoyl chloride (CAS: 1048340-35-7, synthesised with reference to WO 2011158149) (0.5 g, 2.82 mmol) was dissolved in THF (10 mL). Bis(triphenylphosphine)palladium dichloride (0.20 g, 0.28 mmol) was added, and the mixture was purged three times with nitrogen. At room temperature, the above-mentioned reagent was slowly added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 2 h. The reaction was quenched with 20 mL of saturated ammonium chloride and extracted with 20 mL of ethyl acetate and 10 mL of water. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 37A (0.22 g, yield: 27%).

[0444] LCMS m / z = 290.1 [M+H] +< Step 2: Preparation of37B

[0445] Compound 37A (0.22 g, 0.76 mmol) was dissolved in ethylene glycol (3 mL). Hydrazine hydrate (0.38 g, 7.59 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 6 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 37B (0.1 g, yield: 46%).

[0446] LCMS m / z = 284.2 [M+H] +< Step 3: Preparation of37C

[0447] Compound 37B (0.1 g, 0.35 mmol), 2F (0.18 g) and potassium carbonate (0.097 g, 0.70 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 37C (0.15 g, yield: 66%).

[0448] LCMS m / z = 643.1 [M+H] +< Step 4: Preparation of compound 37

[0449] Compound 37C (0.15 g, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.056 g, 2.33 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 37 (90 mg, yield: 62%).

[0450] LCMS m / z = 629.2 [M+H] +<

[0451] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.55 (s, 1H), 9.06 (dd, 1H), 8.72 (dd, 1H), 7.56 - 6.90 (m, 3H), 3.40-3.32 (m, 2H), 2.97 - 2.81 (m, 4H), 1.82 (s, 3H), 1.11 (s, 6H).Preparation of compound 37-1 and compound 37-2:

[0452] Compound 37 (80 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 15%; flow rate: 42 ml / min.

[0453] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0454] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 37-1 (38 mg) and compound 37-2 (35 mg).Compound 37-1: retention time under analysis conditions: 1.9 min, LCMS m / z = 629.2 [M+H] +< Compound 37-2: retention time under analysis conditions: 2.7 min, LCMS m / z = 629.2 [M+H] +< Example 38:

[0455] Step 1: Preparation of 38A

[0456] Compound 2,4-difluoronitrobenzene (1 g, 6.29 mmol) and 2-fluorobenzylamine (0.86 g, 6.88 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (1.22 g, 9.44 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL×3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 5) to obtain compound 38A (1.1 g, yield: 66%).Step 2: Preparation of 38B

[0457] Compound 38A (1.1 g, 4.16 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (2.22 g, 41.49 mmol) and iron powder (2.32 g, 41.56 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 4) to obtain compound 38B (0.8 g, yield: 82%).Step 3: Preparation of38C

[0458] Compound 38B (0.8 g, 3.42 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.83 g, 5.13 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 1) to obtain compound 38C (0.45 g, yield: 50%).

[0459] LCMS m / z = 261.1 [M+H] +< Step 4: Preparation of 38D

[0460] Compound 38C (0.10 g, 0.40 mmol), 2F (0.20 g) and potassium carbonate (0.11 g, 0.80 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 38D (70 mg, yield: 28%).

[0461] LCMS m / z = 620.3 [M+H] +< Step 5: Preparation of compound 38

[0462] Compound 38D (0.07 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.026 g, 1.1 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-50 / 50) to obtain the trifluoroacetate of compound 38 (30 mg).

[0463] LCMS m / z = 606.0 [M+H] +<

[0464] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 7.84 (dd, 1H), 7.41 - 7.32 (m, 1H), 7.31 - 6.98 (m, 7H), 6.94 - 6.87 (m, 1H), 5.15 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.15 - 1.01 (m, 6H).Preparation of compound 38-1 and compound 38-2:

[0465]

[0466] Compound 38 (300 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0467] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 38-1 (110 mg) and compound 38-2 (120 mg).Compound 38-1: retention time under chiral preparative conditions: 7.78 min, LCMS m / z = 606.0 [M+1] +< Compound 38-2: retention time under chiral preparative conditions: 12.85 min, LCMS m / z = 606.2 [M+1] +< Example 39:

[0468]

[0469] With reference to the synthesis for Example 38, the trifluoroacetate of compound 39 (25 mg) was obtained.

[0470] LCMS m / z = 578.2 [M+H] +< Example 40:

[0471] Step 1: Preparation of 40B

[0472] Compound methyl 2-bromo-6-fluorobenzoate (2 g, 8.58 mmol) and 2-fluorophenylacetic acid (1.45 g, 90.48 mmol) were dissolved in THF (40 mL). At - 78°C, sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (60 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 40B (1.8 g, yield: 67%).Step 2: Preparation of 40C

[0473] Compound 40B (1.6 g, 5.14 mmol) was dissolved in methanol (10 mL). Aminoguanidine hydrochloride (0.57 g, 7.71 mmol) and boron trifluoride diethyl etherate (1.1 mL, 8.91 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 40C, which was directly used in the next step.

[0474] LCMS m / z = 367.0[M+H] +< Step 3: Preparation of 40D

[0475] Compound 40C (0.1 g, 0.27 mmol), 21D (0.094 g, 0.27 mmol) and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (15 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 40D (90 mg, yield: 50%).Step 4: Preparation of 40E

[0476] Compound 40D (90 mg, 0.13 mmol) was dissolved in DMF (3 mL). N,N-dimethylethylenediamine (17 mg, 0.19 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 40E (30 mg, yield: 39%).Step 5: Preparation of compound 40

[0477] Compound 40E (0.03 g, 0.051 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.012 g, 0.51 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 40 (10 mg, yield: 34%).

[0478] LCMS m / z = 572.5[M-H] -<

[0479] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 8.67 (d, 1H), 7.75 (s, 1H), 7.56 - 7.46 (m, 1H), 7.33 - 7.25 (m, 1H), 7.24 - 7.16 (m, 2H), 7.14 - 7.00 (m, 2H), 6.96 - 6.74 (m, 2H), 4.43 (s, 2H), 2.71 - 2.61 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H).Example 41:

[0480] Step 1: Preparation of 41B

[0481] Compound 40C (0.1 g, 0.27 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (98 mg, 0.27 mmol) and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (5 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 41B (90 mg, yield: 49%).Step 2: Preparation of 41C

[0482] Compound 41B (90 mg, 0.90 mmol) was dissolved in DMF (3 mL). N,N-dimethylethylenediamine (11 mg, 0.13 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 41C (28 mg, yield: 36%).Step 5: Preparation of compound 41

[0483] Compound 41C (0.028 g, 0.046 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.011 g, 0.46 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 41 (10 mg, yield: 37%).

[0484] LCMS m / z = 588.5[M-H] -<

[0485] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 8.68 (d, 1H), 7.56 - 7.48 (m, 1H), 7.33 - 7.02 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 41-1 and compound 41-2:

[0486]

[0487] Compound 41 (90 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 45%; c. flow rate: 44 ml / min.

[0488] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 41-1 (40 mg) and compound 41-2 (40 mg).Compound 41-1: retention time under chiral preparative conditions: 4.53 min, LCMS m / z = 590.5 [M+H] +<

[0489] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 8.68 (d, 1H), 7.57 - 7.43 (m, 1H), 7.35 - 6.98 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Compound 41-2: retention time under chiral preparative conditions: 23.08 min, LCMS m / z = 590.5 [M+H] +<

[0490] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 8.68 (d, 1H), 7.59 - 7.43 (m, 1H), 7.36 - 6.93 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 42:

[0491]

[0492] With reference to the synthesis for Example 40, compound 42 (10 mg) was obtained.

[0493] LCMS m / z = 592.2[M+H] +<

[0494] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 8.67 (d, 1H), 7.75 (s, 1H), 7.57 - 7.48 (m, 1H), 7.37 - 7.25 (m, 1H), 7.16 - 6.99 (m, 3H), 6.99 - 6.68 (m, 2H), 4.48 (s, 2H), 2.71 - 2.61 (m, 2H), 1.82 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 43:

[0495] Step 1: Preparation of 43B

[0496] Compound 40A (2 g, 8.58 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (3.3 g, 17 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (18 mL, 2 M, 36 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (160 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 43B (0.6 g, yield: 20%).Step 2: Preparation of 43C

[0497] Compound 43B (0.6 g, 1.72 mmol) was dissolved in methanol (20 mL). Aminoguanidine hydrochloride (0.38 g, 3.44 mmol) and boron trifluoride diethyl etherate (0.49 g, 3.44 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43C (0.3 g, yield: 43%).Step 3: Preparation of 43D

[0498] Compound 43C (0.34 g, 0.83 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (300 mg, 0.83 mmol) and potassium bicarbonate (83 mg, 0.83 mmol) were mixed and dissolved in tert-butanol (5 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43D (200 mg, yield: 34%).

[0499] LCMS m / z = 722.1[M+H] +< Step 4: Preparation of 43E

[0500] Compound 43D (200 mg, 0.28 mmol) was dissolved in DMF (5 mL). N,N-dimethylethylenediamine (37 mg, 0.42 mmol) and cuprous iodide (53 mg, 0.28 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43E (120 mg, yield: 68%).

[0501] LCMS m / z = 642.2[M+H] +< Step 5: Preparation of compound 43

[0502] Compound 43E (0.12 g, 0.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.011 g, 0.46 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 43 (40 mg).

[0503] LCMS m / z = 628.2[M+H] +<

[0504] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.68 (d, 1H), 7.61 - 7.46 (m, 1H), 7.25 (s, 1H), 7.22 - 6.96 (m, 3H), 3.42 - 3.28 (m, 2H), 2.93 (s, 2H), 2.85 - 2.69 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).

[0505] The racemate of compound 43 (130 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 22%; c. flow rate: 43 ml / min.

[0506] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 43-1 (60 mg) and compound 43-2 (60 mg). Compound 43-1: retention time under chiral preparative conditions: 4.05 min, LCMS m / z = 628.2 [M+H] +<

[0507] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.68 (d, 1H), 7.58 - 7.49 (m, 1H), 7.25 (s, 1H), 7.22 - 6.98 (m, 3H), 3.39 - 3.32 (m, 2H), 2.94 (s, 2H), 2.88 - 2.64 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Compound 43-2: retention time under chiral preparative conditions: 9.87 min, LCMS m / z = 628.2 [M+H] +<

[0508] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.68 (d, 1H), 7.58 - 7.48 (m, 1H), 7.25 (s, 1H), 7.22 - 6.95 (m, 3H), 3.40 - 3.32 (m, 2H), 2.94 (s, 2H), 2.86 - 2.67 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Example 44:

[0509]

[0510] With reference to the synthesis for Example 35, compound 44 (50 mg) was obtained.

[0511] LCMS m / z = 579.3 [M+H] +< Example 45:

[0512] Step 1: Preparation of 45A

[0513] To a reaction flask were added 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-carboxamide (CAS: 1407815-26-2, 0.2 g, 0.62 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2,0.23 g, 0.62 mmol), sodium bicarbonate (0.21 g, 2.48 mmol) and tert-butanol (10 mL). The mixture was heated and reacted overnight in an oil bath at 85°. To the reaction solution was added an appropriate amount of silica gel, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 45A (0.23 g, yield: 58%).Step 2: Preparation of compound 45

[0514] To a reaction flask were added 45A (0.23 g, 0.36 mmol), lithium hydroxide monohydrate (0.15 g, 3.60 mmol), 1,4-dioxane (5 mL) and water (3 mL). The mixture was stirred overnight at room temperature reaction. Ethyl acetate and water were added, and the mixture was adjusted to pH 2-3 with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain compound 45 (0.19 g, yield: 84%).

[0515] LCMS m / z = 628.0[M+H] +<

[0516] Compound 45 (180 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 25%; c. flow rate: 40 ml / min.

[0517] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 45-1 (72 mg) and compound 45-2 (70 mg). Compound 45-1: retention time under chiral preparative conditions: 8.1 min, LCMS m / z = 628.3[M+H] +<

[0518] 1< H NMR (400 MHz, CDCl 3 / CD 3 OD(v / v) = 1 / 1) δ 8.68 (dd, 1H), 8.16 - 8.05 (m, 1H), 7.14 - 6.91 (m, 2H), 3.33 - 3.28 (m, 2H), 3.13 - 2.98 (m, 2H), 2.94 - 2.76 (m, 2H), 1.88 (s, 3H), 1.24 (s, 3H), 1.21 (s, 3H).Compound 45-2: retention time under chiral preparative conditions: 27.1 min, LCMS m / z = 628.3[M+H] +<

[0519] 1< H NMR (400 MHz, CDCl 3 / CD 3 OD(v / v) = 1 / 1) δ 8.68 (dd, 1H), 8.09 - 7.93 (m, 1H), 7.12 - 6.90 (m, 2H), 3.34 - 3.25 (m, 2H), 3.14 - 2.98 (m, 2H), 2.94 - 2.74 (m, 2H), 1.88 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H).Example 46:

[0520] Step 1: Preparation of 46A

[0521] To a reaction flask were added 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-carboxamide (CAS: 1407815-26-2, 0.16 g, 0.49 mmol), 21D (0.17 g, 0.49 mmol), sodium bicarbonate (0.16 g, 1.96 mmol) and tert-butanol (10 mL). The mixture was heated and reacted overnight in an oil bath at 85°C. To the reaction solution was added an appropriate amount of silica gel, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 46A (0.23 g, yield: 75%).Step 2: Preparation of compound 46

[0522] To a reaction flask were added 46A (0.21 g, 0.34 mmol), lithium hydroxide monohydrate (0.14 g, 3.40 mmol), 1,4-dioxane (5 mL) and water (3 mL). The mixture was stirred overnight at room temperature reaction. Ethyl acetate and water were added, and the mixture was adjusted to pH 2-3 with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain compound 46 (0.18 g, yield: 88%).

[0523] LCMS m / z = 612.2[M+H] +< Example 47:

[0524] Step 1: Preparation of 47A

[0525] Compound 2-(aminomethyl)-5-chloropyridine hydrochloride (1.00 g, 5.59 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.61 g, 8.38 mmol) were dissolved in DMF (20 mL). HATU (4.25 g, 11.18 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (3.61 g, 27.95 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 100 / 0-100 / 30) to obtain compound 47A (1.7 g, yield: 96%).Step 2: Preparation of 47B

[0526] Compound 47A (1.7 g, 5.37 mmol) was dissolved in phosphorus oxychloride (20 mL), and the mixture was warmed to reflux and reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 47B (1.6 g).

[0527] LCMS m / z = 299.1 [M+H] +< Step 3: Preparation of 47C

[0528] Compound 47B (1.7 g, 5.69 mmol) was dissolved in DCM (20 mL). NBS (1.14 g, 6.26 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 47C (2.1 g).Step 4: Preparation of 47D

[0529] Compound 47C (2 g, 5.30 mmol) and zinc cyanide (1.24 g, 10.6 mmol) were added to a 50 mL single-necked flask, and then zinc powder (693.35 mg, 10.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.76 g, 3.18 mmol), tris(dibenzylidene-BASE acetone)dipalladium (1.46 g, 1.59 mmol) and N,N-dimethylacetamide (30 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 100 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain compound 47D (400 mg, yield: 23%).

[0530] LCMS m / z = 324.0 [M+H] +< Step 5: Preparation of 47E

[0531] In an ice bath, ammonium chloride (190 mg, 3.55 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (1.77 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 47D (230 mg, 0.71 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 47E (145 mg, yield: 60%).Step 6: Preparation of 47F

[0532] Compound 47E (140 mg, 0.41 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (149 mg, 0.41 mmol) and sodium bicarbonate (137.78 mg, 1.64 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 20 / 1) to obtain compound 47F (120 mg, yield: 44%).

[0533] LCMS m / z = 658.2 [M+H] +< Step 7: Preparation of compound 47

[0534] Compound 47F (120 mg, 0.18 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL). Lithium hydroxide hydrate (76 mg, 1.8 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 47 (68 mg, yield: 58%)

[0535] LCMS m / z = 644.1 [M+H] +< Compounds 47-1 and 47-2

[0536]

[0537] The racemate of compound 47 (68 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 40%; c. flow rate: 41 ml / min.

[0538] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 47-1 (30 mg) and compound 47-2 (30 mg).Compound 47-1: retention time under chiral preparative conditions: 4.85 min, LCMS m / z = 644.5 [M+H] +<

[0539] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.30 - 11.96 (m, 1H), 11.31 (s, 1H), 8.72 - 8.62 (m, 2H), 7.23 (s, 1H), 7.12 - 7.02 (m, 1H), 6.83 - 6.67 (m, 2H), 3.39 - 3.32 (m, 2H), 2.99 - 2.78 (m, 4H), 1.78 (s, 3H), 1.11 (s, 6H).Compound 47-2: retention time under chiral preparative conditions: 19.15 min, LCMS m / z = 644.5 [M+H] +<

[0540] 1< H NMR (400 MHz, DMSO -d 6 ) δ 12.36 - 12.01 (m, 1H), 11.31 (s, 1H), 8.78 - 8.58 (m, 2H), 7.23 (s, 1H), 7.11 - 7.01 (m, 1H), 6.82 - 6.66 (m, 2H), 3.41 - 3.31 (m, 2H), 3.00 - 2.76 (m, 4H), 1.79 (s, 3H), 1.11 (s, 6H). Control compound 1 : compound 77B in WO2017112617 Biological test examples 1. cGMP detection experiment in CHO-KI / sGC cells

[0541] Stably-transfected CHO-K1 cells stably expressing sGC α1 / β1 heterodimers were constructed and named CHO-KI / sGC. The CHO-KI / sGC cells were cultured in a complete medium (FK12+10% FBS+1% penicillin-streptomycin+0.5 mg / mL hygromycin+ 0.25 mg / mL G418). On the day of the detection, the cells were reselected in EAB assay buffer (EBSS assay buffer+5 mL of MgCl2+10 mM HEPES+0.05% BSA) at a density of 2.25*10 5< / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0542] The cells were pre-incubated with 1 pM diethylenetriamine / nitric oxide (EDTA-NO) at room temperature for 30 minutes, and then different concentrations of the compounds were added. The mixture was further incubated at 37°C for 1 h. After the incubation was completed, the reaction was terminated, and intracellular cGMP levels were measured according to the instructions for the Cisbio kit (CisBio, 62GM2PEC). The maximum cGMP production relative to the positive compound was calculated according to Equation (1-1), where RLU compound represents the reading of the test compound, and RLU reference represents the maximum reading of the positive compound. Activion % = RLU compound / RUL reference * 100 %

[0543] Conclusion: The compounds of the present invention, such as the example compounds, have good stimulatory effects on cGMP production in CHO-KI / sGC cells.2. In vitro detection experiment for soluble guanylate cyclase (sGC) activity

[0544] First, 100 nL of the compounds at different concentrations were transferred to a 384-well reaction plate (Greiner, Cat. No. 784075) using Echo 655 (LABCYTE, Cat # 655), with the final DMSO concentration of 1% in the reaction mixture; 2 µL of sGC (ICE, Cat. No. S2304F-H07SH2) was added to a 384-well reaction plate, and the mixture was centrifuged at 1000 rpm for 1 min; and then 1 µL of DETA NONOate was added, and the mixture was incubated at 37°C for10 min. After the incubation was completed, 2 µL of GTP was added, and the mixture was centrifuged at 1000 rpm for 1 min and reacted at 37°C for 60 min. In the reaction system, the final concentrations of sGC, GTP, and DETA NONOate were 1.5 nM, 5 µM, and 100 µM, respectively. After the reaction was completed, 5 µL of the test mixture (PerkinElmer, Cat. No. 62GM2PEG) was added and incubated at room temperature for 60 min. The TR-FRET signal (Ratio: 665 / 620 nm) was read using a microplate reader (BMG, Cat. No. PHERAstar FSX). A nonlinear regression curve was fitted using GraphPad Prism software, and EC 50 values were calculated. Compound A (Example 1 in WO 2010065275) was used as a positive reference compound. The activation rate was calculated according to Equation 2-1, where Low control represents the TR-FRET signal value of 1 µM compound A, and High control represents the TR-FRET signal value in the DMSO well. Table 2-1 Results of enzymatic agonism and / or activation of test compounds on soluble guanylate cyclase (sGC).Compound No.EC 50 (nM)Compound No.EC 50 (nM)Compound 1-2ATrifluoroacetate of compound 23ACompound 3ACompound 24ATrifluoroacetate of compound 4ATrifluoroacetate of compound 27ATrifluoroacetate of compound 5ATrifluoroacetate of compound 28ACompound 8ACompound 29ACompound 9ACompound 31ATrifluoroacetate of compound 10ATrifluoroacetate of compound 32ACompound 11ATrifluoroacetate of compound 33ACompound 12ATrifluoroacetate of compound 34ACompound 13ACompound 35ATrifluoroacetate of compound 14ACompound 36ATrifluoroacetate of compound 15ACompound 37ACompound 16ATrifluoroacetate of compound 38ACompound 17ATrifluoroacetate of compound 39ACompound 18ACompound 40ACompound 19ACompound 41ACompound 20ACompound 42ACompound 21ACompound 44ACompound 46ACompound 45ANote: A < 20 nM, 20 nM ≤ B < 50 nM, 50 nM ≤ C < 200 nM

[0545] Conclusion: The compounds of the present invention, such as the example compounds, have good agonistic and / or activating effects on the enzyme activity of soluble guanylate cyclase (sGC).3. cGMP detection experiment in LNCap cells

[0546] LNCap is a human prostate cancer cell line that expresses sGC protein. LNCap cells were purchased from ATCC and cultured in a complete medium (RPMI-1640+10% FBS+1% PS). On the day of the detection, the cells were reselected in assay buffer (EBSS assay buffer+5 mL of MgCl2+10 mM HEPES+0.05% BSA) at a density of 2 × 10 5< / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0547] The cells were pre-incubated with 20 µM diethylenetriamine / nitric oxide (DETA-NO) at 37°C for 30 minutes, and then different concentrations of the compounds were added. The mixture was further incubated at room temperature for 1 h. After the incubation was completed, the reaction was terminated, and intracellular cGMP levels were measured according to the instructions for the CisBio kit (Cisbio, 62GM2PEC). The cGMP production relative to compound A (Example 1 in WO 2010065275) was calculated according to Equation (3-1), and EC 50 values were calculated. Sample cGMP represents the reading of the test compound, Low control GMP represents the 1% DMSO control, and High control cGMP represents the maximum cGMP reading of compound A. Table 3-1. Results of stimulatory effects of test compounds on cGMP production in LNCap cellsCompound No.EC 50 (nM)Compound 4-1<500Compound 14-1<500Compound 15-1<500Compound 17-1<500Trifluoroacetate of compound 27<500Compound 31-1<500Compound 32-1<500Compound 35-1<500Compound 41-1<500Compound 43-1<500Control compound 13220

[0548] Conclusion: The compounds of the present invention, such as the example compounds, have good stimulatory effects on cGMP production in LNCap cells.4: Pharmacokinetic test in rats (inhalation administration)

[0549] Experimental objective: In this experiment, the test compound was administered as a single dose via inhalation to SD rats, and the concentrations of the test compound in rat plasma and lungs were determined to evaluate the pharmacokinetic characteristics and bioavailability of the test compound in the rats.

[0550] Experimental animals: Male SD rats, 180-200 g, purchased from Chengdu Dossy Experimental Animals Co., Ltd.

[0551] Experimental method: On the day of the experiment, SD rats were randomly assigned into 6 groups according to body weight (for each compound), with 2 rats in each group. The rats were fasted with water available for 12 to 16 hours one day before the administration, and were fed 4 hours after the administration. Administration informationTest compoundAdministrati on dosage* (mg / kg)Administrati on concentration (mg / mL)Administrati on volume (mL / kg)Collected sampleMode of administra tionVehicleCompound of the present invention0.030.031Plasma or lung tissueInhalationDMA+HS-15(Solutol) +Saline*Dosage is calculated based on free base. (DMA: dimethylacetamide; HS-15(Solutol): polyethylene glycol-15-hydroxystearate; saline: physiological saline)

[0552] Plasma sampling: before and after the administration, blood was taken from the orbits of the rats under isoflurane anaesthesia, and placed in an EDTAK 2 centrifuge tube. Centrifugation was performed at 6000 rpm at 4°C for 10 min, and the plasma was collected. Time points for plasma collection comprise 0, 0.0833, 0.25, 0.5, 1, 2, 4, 7 and 24 h.

[0553] Lung tissue sampling: Animals from each group were euthanised by CO 2 inhalation at 0.25, 0.5, 1, 4, 7 and 24 hours after the administration. Then, the animal was dissected to collect lung tissue, which was rinsed with physiological saline, dried with filter paper, weighed in the balance, kept on wet ice and homogenised within 2 hours using a 6-fold volume (i.e., 6 mL per 1 g of tissue) of homogenisation buffer (50% methanol-water).

[0554] Before analysis and detection, all samples were stored at -60°C. The samples were analysed quantitatively by LC-MS / MS. Table 4-1 Pharmacokinetic parameters of test compounds in rats (inhalation administration)Test compoundLung AUC 0-t (h.ng. mL -1< )Lung AUC 0-t / plasma AUC 0-t Lung Cmax (ng / mL)Compound 3-13626652979Compound 4-1246277.12352Compound 6-151736592825Compound 17-1202148.41754Compound 19-1122482452842Compound 31-160897.91183Compound 35-15432 / 2545Compound 36-11013349.14067Compound 37-13281 / 1729Compound 38-1 / 83.61743Compound 45-1450043.42846Control compound 122029.1273

[0555] Conclusion: The compounds of the present invention, such as the example compounds, have good exposure levels and / or lung-to-plasma ratios in the lungs of rats after inhalation administration.5. Test for hERG potassium ion channel Experimental platform: Electrophysiological manual patch-clamp system

[0556] Cell line: Chinese hamster ovary (CHO) cell lines stably expressing hERG potassium ion channel

[0557] Experimental method: In CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, whole cell patch-clamp technique was used to record hERG potassium channel current at room temperature. The glass microelectrode was made of a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after filling the liquid in the electrode was about 2-5 MΩ. The glass microelectrode can be connected to the patch-clamp amplifier by inserting the glass microelectrode into an amplifier probe. The clamping voltage and data recording were controlled and recorded by the pClamp 10 software through a computer. The sampling frequency was 10 kHz, and the filtering frequency was 2 kHz. After the whole cell records were obtained, the cells were clamped at -80 mV, and the step voltage that induced the hERG potassium current (I hERG ) was depolarised from -80 mV to +20 mV for 2 s, then repolarised to -50 mV, and returned to -80 mV after 1 s. This voltage stimulation was given every 10 s, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute). The compound was administered for at least 1 minute at each test concentration, and at least 2 cells (n ≥ 2) were tested at each concentration.

[0558] Data processing: Data analysis processing was carried out by using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition degree of hERG potassium current (peak value of hERG tail current induced at -50 mV) at different compound concentrations was calculated by the following formula: Inhibition % = 1 − I / I o × 100 % where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current after and before the administration, respectively.

[0559] Compound IC 50 was calculated using GraphPad Prism 5 software by fitting according to the following equation: Y = Bottom + Top − Bottom / 1 + 10 ∧ LogIC 50 − X * HillSlope where X represents the Log value of the tested concentration of the test compound, Y represents the percentage inhibition at the corresponding concentration, and Bottom and Top represent the minimum and maximum percentage inhibitions, respectively.

[0560] Conclusion: The compounds of the present invention have no obvious inhibitory effects on the hERG potassium ion channel.6. CYP450 enzyme inhibition test

[0561] The objective of this study was to evaluate the effects of test compounds on the activity of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) by using an in vitro testing system. The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test compounds of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the sample was treated and liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to quantitatively detect metabolites produced by specific substrates, changes in CYP enzyme activity were determined, and IC 50 value was calculated to evaluate the inhibitory potential of the test compound on each CYP enzyme subtype.

[0562] Conclusion: The compounds of the present invention have no significant or only weak inhibitory effects on CYP450 enzymes.7. Pharmacodynamic study on relaxation of thoracic aortic vascular rings in SD rats

[0563] Male SD rats, 8 weeks old and of SPF grade, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The animals were acclimatised for at least one week upon arrival at the animal facility. Prior to the experiment, the rats were weighed and randomly assigned to groups based on body weight. On the day of the experiment, the rats were deeply anesthetised with Zoletil 50 (20 mg / kg, i.p.) and Xylazine (8 mg / kg, i.p.). The thoracic cavity was quickly opened, and the aorta was carefully isolated. A segment of the descending aorta was excised and placed in a petri dish containing a K-H solution saturated with carbogen (95% O 2 +5% CO 2 ). After removing connective tissue surrounding the vessel, vascular rings of approximately 3-5 mm in length were prepared. The vascular rings were suspended using custom-made hooks in an isolated tissue perfusion bath containing a 37°C K-H solution. The bath was aerated with carbogen, and connected to a force transducer (Chengdu Instrument Factory, JZ101H). The force transducer was connected to a multichannel electrophysiological signal recording system (Chengdu Instrument Factory, RM6240E). The vascular rings were rinsed with a K-H solution and equilibrated for 90 minutes under a resting tension of 3 g. Subsequently, the vascular rings were pre-contracted with 10 -6< M norepinephrine in the bath until a stable tension was achieved. The test compound was then added to the bath in a cumulative concentration-gradient manner (from low to high) to induce vasodilation, with a 5-minute interval between each addition. The changes in tension of the thoracic aortic vascular rings were observed. The percentage of relaxation was calculated for each concentration.

[0564] Conclusion: The compounds of the present invention, such as the example compounds, have significant vasodilatory effects in rat thoracic aortic vascular rings.8. SHR rat telemetric blood pressure monitoring

[0565] Surgical implantation of blood pressure telemetry transmitter: one day prior to surgery, the DSI transmitter was sterilised by immersion in a 2% glutaraldehyde solution for 8-10 h; animals were weighed, and anesthetised with Xylazine (8 mg / kg, i.p.) and Zoletil 50 (20 mg / kg, i.p.); and the animals were fasted overnight before the procedure. The implantation procedure was performed on Day 1 of the study, as detailed below. The abdominal skin was aseptically disinfected, and a longitudinal incision was made. The abdominal organs were dissected to expose the abdominal aorta. The pressure-sensing catheter of the transmitter was inserted into the abdominal aorta. Haemostasis and closure of the surgical site were achieved with bioadhesives, and then the transmitter body was secured to the abdominal wall. The muscle and skin layers were sutured, the surgical site was disinfected, and meloxicam was administered subcutaneously for analgesia. Following surgery, the animals were recovered in a 37°C incubator until resumption of voluntary motor activity, and then singly housed in their cages. For the first three postoperative days, the animals received daily subcutaneous injections of gentamicin sulphate (4-8 mg / kg) for infection prophylaxis and meloxicam for analgesia.

[0566] Blood pressure monitoring: After approximately 10 days of postoperative recovery, baseline blood pressure was recorded over a 24-hour period. Rats were assigned to groups based on baseline blood pressure. Following grouping, the rats were administered (either orally or via IT). After a single administration, blood pressure was monitored for 24 hours, during which changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were recorded. Raw data were used to calculate the mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean heart rate at regular intervals (conventionally set at 30 minutes). A p-value of less than 0.05 was considered statistically significant.

[0567] Conclusion: The compounds of the present invention, such as the example compounds, have significant blood pressure-lowering effects in rats, while no significant reduction in abdominal aortic pressure was observed following the IT administration.

Examples

example 1

Example 1 :

[0071]

Step 1: Preparation of 1A

[0072]Compound isobutyryl chloride (7 g, 65.67 mmol) was dissolved in THF (40 mL), and the mixture was cooled to -70°C. A solution of potassium tert-butoxide in tetrahydrofuran (72 mL, 1 N) was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min, and then 100 mL of water and 50 mL of methyl tert-butyl ether were added sequentially. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.

Step 2: Preparation of 1B

[0073]Compound 1A (7.77 g, 53.89 mmol) was dissolved in THF (80 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of LDA in tetrahydrofuran (80 mL, 1 N) was slowly added dropwise. After the addition, the mixture was further stirred for 30 min, warmed to 0°C and then st...

example 2

[0099]

Step 1: Preparation of 2A

[0100]Compound diethyl 2-(dicyanomethyl)-2-methylmalonate (CAS: 1350855-72-9) (1 g, 4.20 mmol), S-methylisothiourea sulphate (0.79 g, 4.2 mmol) and potassium bicarbonate (1.68 g, 16.78 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate was added, and the mixture was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 2A (0.9 g, yield: 76%).

[0101]LCMS m / z = 283.20 [M+H] +<

Step 2: Preparation of 2B

[0102]Compound 2A (0.9 g, 3.19 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (10 mL, 7 N) was added, and the mixture was warmed to 40°C, stirred overnight, cooled to room temperature and concentrated unde...

example 3

[0119]

Step 1: Preparation of3A

[0120]Pyridazine (3 g, 37.50 mmol) was dissolved in chloroform (60 mL). Trifluoromethanesulphonic anhydride (12.59 g, 44.63 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. Trimethylsilyl cyanide (15.81 g, 159.26 mmol) was added, and the mixture was warmed to 60°C, reacted for 3 h and cooled. Then, N-methyl morpholine (4.93 g, 48.75 mmol) was added, and the mixture was warmed to 60°C again, reacted overnight and cooled to room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted twice with DCM. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 13) to obtain compound 3A (2.5 g, yield: 63%).

[0121]LCMS m / z = 106.20 [M+H] +<

Step 2: Preparation of 3B hydrochloride

[0122]Compound 3A (2 g, 19.03 mmol) was dissolved in...

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically discloses a compound represented by formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and the use thereof in the preparation of a drug for treating sGC-related diseases.Background Art

[0002] Nitric oxide (NO) signalling has pleiotropic effects in biology and plays a critical function in cardiovascular homeostasis. An increase in NO secretion occurs under the influence of mediators, such as norepinephrine (NA), angiotensin, adenosine triphosphate, or bradykinin. NO synthesis is also stimulated as a result of numerous physical factors (Int. J. Mol. Sci. 2021, 22, 6029; Molecules 2021, 26, 3418).

[0003] The mechanism of NO's intracellular action is primarily through the stimulation of the activity of soluble guanylyl cyclase (sGC). The sGC is heme-containing enzyme, which causes an increase in the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vascular relaxation (Nat. Rev. Cardiol. 2018, 15,292-316). The NO / sGC / cGMP regulatory pathway plays a leading role in the homeostasis of the cardiovascular and pulmonary systems and organs (such as the kidney, brain, and liver). In addition to smooth muscle cells, cGMP influences the function of fibroblasts, cardiomyocytes, platelets, neurons, and immune cells, regulating the processes of fibrosis, inflammatory response, and neurotransmission (Molecules 2023, 28, 861).

[0004] sGC modulators and sGC agonists are a class of drugs that can stimulate cGMP formation, and provide tools for studying the regulatory mechanisms of sGC and its role in pathological mechanisms. The development of sGC modulators or agonists has made it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs (Molecules 2023, 28, 861). Riociguat is the first approved sGC agonist. In 2013, Riociguat was approved for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH) (J. Med. Chem. 2017, 60, 5146-5161). In the 12-week, multicentre, double-blind, randomised, placebo-controlled, pivotal PATENT-1 study, the most common AEs (occurring in ≥ 3% of patients) that were reported more frequently in the riociguat group than in the placebo group were headache (27% vs. 18%), dyspepsia / gastritis (21% vs. 8%), dizziness (20% vs. 13%), nausea (14% vs. 11%), diarrhoea (12% vs. 8%), hypotension (10% vs. 4%), vomiting (10% vs. 7%), anaemia (7% vs. 2%), gastrooesophageal reflux disease (5% vs. 2%), and constipation (5% vs. 1%). The development of novel sGC modulators or agonists to improve therapeutic effects or reduce toxic and side effects has good application prospects.Summary of the Invention

[0005] The objective of the present invention is to provide a compound having a novel structure and represented by general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating sGC-related diseases.

[0006] The compounds of the present invention have good stimulatory effects on cGMP production in LNCap cells and exhibit excellent lung pharmacokinetic properties, e.g., superior lung AUC and / or lung-to-plasma ratios compared to control 1, thereby conferring the advantages of lung targeting and reduced systemic side effects.

[0007] The present invention provides a compound represented by general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in some embodiments, the compound represented by general formula (I) is a compound represented by general formula (II), in some embodiments, the compound represented by general formula (I) or (II) is a compound represented by general formula (III-1) or (III-2), in some embodiments, R is selected from in some embodiments, R is selected from in some embodiments, Z is selected from CH or N; in some embodiments, Z 1 or Z 2 is each independently selected from CH or N, and at least one of Z 1 and Z 2 is N; in some embodiments, X 1 or X 2 is each independently selected from O or S; in some embodiments, A is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl; in some embodiments, A is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; in some embodiments, A is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; in some embodiments, A is selected from the following groups optionally substituted with 1 to 4 R a< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, A is selected from the following groups optionally substituted with 1 to 4 R a< : phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R 1< is -M-(CR 1a< R 1b< ) r -(CR 1c< R 1d< ) s -COOH; in some embodiments, R 1< is selected from in some embodiments, M is selected from a bond, C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; in some embodiments, M is selected from a bond, or the following groups optionally substituted with 1 to 4 R m< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R 2< is selected from C 1-6 alkyl or C 1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 R k< ; in some embodiments, R 2< is selected from C 1-5 alkyl or C 1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 R k< ; in some embodiments, R 2< is selected from C 1-4 alkyl or C 1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 R k< ; in some embodiments, R 2< is selected from methyl, ethyl, propyl, butyl, - methylene-Q, -ethylene-Q, or -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, or propylene is optionally substituted with 1 to 6 R k< ; in some embodiments, R 2< is selected from in some embodiments, Q is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; in some embodiments, Q is selected from the following groups optionally substituted with 1 to 4 R q< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; in some embodiments, R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; in some embodiments, R a< , R c< , and R b3< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-11 cycloalkyl or 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form the following groups optionally substituted with 1 to 4 R k< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, or tetrahydropyranyl; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; in some embodiments, R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, or cyclopropyl; in some embodiments, each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3-to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy; in some embodiments, each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3-to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; in some embodiments, each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; in some embodiments, each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , methyl, ethyl, methoxy, or ethoxy; in some embodiments, a, c, r, and s are each independently selected from 0, 1, 2, 3, or 4; in some embodiments, a and c are each independently selected from 0, 1 or 2; in some embodiments, c is selected from 0, 1 or 2.

[0008] A first embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein R is selected from or Z is selected from CH or N; Z 1 or Z 2 is each independently selected from CH or N, and at least one of Z 1 and Z 2 is N; X 1 or X 2 is each independently selected from O or S; A is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl; R 1< is -M-(CR 1a< R 1b< ) r -(CR 1c< R 1d< ) s -COOH; M is selected from a bond, C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-6 alkyl or C 1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 R k< ; Q is selected from C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, or -C 0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy; a, c, r, and s are each independently selected from 0, 1, 2, 3, or 4.

[0009] A second embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-5 alkyl or C 1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 R k< ; Q is selected from C 3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, halogen, OH, CN, NH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-11 cycloalkyl or 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k< ; each R k< is independently selected from H, deuterium, halogen, OH, =O, CN, NH 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -O-C 3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, or -C 0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; the remaining definitions are the same as those in the first embodiment of the present invention.

[0010] A third embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R m< ; R 2< is selected from C 1-4 alkyl or C 1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 R k< ; Q is selected from C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 R q< ; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form C 3-7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k< ; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or the following groups optionally substituted with 1 to 4 R k< : methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, or C 1-4 alkoxy; the remaining definitions are the same as those in the first or second embodiment of the present invention.

[0011] A fourth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from the following groups optionally substituted with 1 to 4 R a< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; M is selected from a bond, or the following groups optionally substituted with 1 to 4 R m< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R 2< is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, or -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, or propylene is optionally substituted with 1 to 6 R k< ; Q is selected from the following groups optionally substituted with 1 to 4 R q< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R a< , R c< , R m< , R q< , R b3< , R 1a< , R 1b< , R 1c< , and R 1d< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; alternatively, R 1a< and R 1b< or R 1c< and R 1d< respectively taken together with the carbon atom to which they are attached form the following groups optionally substituted with 1 to 4 R k< : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, or tetrahydropyranyl; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 R k< ; each R k< is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH 2 , COOH, CONH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , methyl, ethyl, methoxy, or ethoxy; the remaining definitions are the same as those in the first, second, or third embodiment of the present invention.

[0012] A fifth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein A is selected from the following groups optionally substituted with 1 to 4 R a< : phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R 1< is selected from R is selected from R 2< is selected from or R a< , R c< , and R b3< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; R b1< , R b2< , and R b4< are each independently selected from H, deuterium, OH, CN, NH 2 , methyl, ethyl, methoxy, or cyclopropyl; c is selected from 0, 1 or 2; the remaining definitions are the same as those in the first, second, third, or fourth embodiment of the present invention.

[0013] A sixth embodiment of the present invention provides the above-described compound represented by general formula (I) or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound represented by general formula (I) is a compound represented by general formula (II), wherein A is selected from the following groups: phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R is selected from R 2< is selected from or R a< and R c< are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , CHF 2 , CH 2 F, methyl, ethyl, methoxy, or cyclopropyl; a and c are each independently selected from 0, 1 or 2.

[0014] A seventh embodiment of the present invention provides the above-described compound represented by general formula (I) or (II), or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound represented by general formula (I) or (II) is a compound represented by general formula (III-1) or (III-2), wherein the remaining definitions are the same as the corresponding definitions in any one of the first to sixth embodiments of the present invention.

[0015] The present invention relates to a compound as described below or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound has a structure selected from one of those in Table E-1 below:

[0016] The present invention relates to a pharmaceutical composition comprising the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

[0017] The present invention relates to the use of the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the above-described pharmaceutical composition in the preparation of a drug for treating sGC-related diseases.

[0018] The present invention relates to the use of the above-described compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the above-described pharmaceutical composition in the preparation of a drug for treating cardiovascular diseases, kidney diseases or respiratory diseases, preferably pulmonary arterial hypertension, pulmonary hypertension or chronic obstructive pulmonary disease.

[0019] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and a pharmaceutically acceptable excipient. The pharmaceutical composition can be in a unit dosage form (the amount of the active pharmaceutical ingredient per unit dosage form is also referred to as the "dosage strength").

[0020] The present invention also provides a method for treating a disease in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof or the pharmaceutical composition according to the present invention. In some embodiments, the mammal described in the present invention comprises human.

[0021] The term "effective amount" or "therapeutically effective amount" in the present application refers to a sufficient amount of the compound disclosed in the present application that is administered to ameliorate, to some extent, one or more symptoms of a disease or condition being treated (e.g., a cardiovascular disease). In some embodiments, the outcome is the reduction and / or remission of signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" in terms of the therapeutic use is an amount of the included compound disclosed in the present application that is required to provide clinically significant reduction of the symptoms of the disease. Examples of the therapeutically effective amount include, but are not limited to 0.01-1500 mg, 0.01-1000 mg, 0.01-800 mg, 0.01-600 mg, 0.1-1500 mg, 0.1-1000 mg, 0.1-800 mg, 0.1-600 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 6-500 mg, 10-500 mg, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, 60-500 mg, 70-500 mg, 75-500 mg, 80-500 mg, 90-500 mg, 100-500 mg, 125-500 mg, 150-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 400-500 mg, 5-400 mg, 10-400 mg, 20-400 mg, 25-400 mg, 30-400 mg, 40-400 mg, 50-400 mg, 60-400 mg, 70-400 mg, 75-400 mg, 80-400 mg, 90-400 mg, 100-400 mg, 125-400 mg, 150-400 mg, 200-400 mg, 250-400 mg, 300-400 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 40-300 mg, 50-300 mg, 60-300 mg, 70-300 mg, 75-300 mg, 80-300 mg, 90-300 mg, 100-300 mg, 125-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 1-200 mg, 2-200 mg, 5-200 mg, 10-200 mg, 20-200 mg, 25-200 mg, 30-200 mg, 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 0.01-100 mg, 0.01-50 mg, 0.01-10 mg, 0.01-5 mg, 0.05-10 mg, 0.05-5 mg, 0.1-5 mg, 1-5 mg, 0.1-1 mg, or 0.1-5 mg; in some embodiments, the pharmaceutical composition comprises, but not limited to 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, or 300 mg of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention.

[0022] A method for treating a disease in a mammal, wherein the method comprises administering to a subject a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, wherein the therapeutically effective amount is preferably 0.01-1500 mg, and the disease is preferably a cardiovascular disease.

[0023] A method for treating a disease in a mammal, wherein the method comprises administering to a subject the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention at a daily dose of 0.01-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 0.01-1500 mg / day, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 0.01 mg / day, 0.05 mg / day, 0.1 mg / day, 0.15 mg / day, 0.2 mg / day, 0.3 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, or 800 mg / day.

[0024] The present invention relates to a kit which can comprise a composition in single-dose or multi-dose form, wherein the kit comprises the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and the amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is the same as the amount in the above-described pharmaceutical composition.

[0025] In the present invention, the amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is calculated in the form of a free base in each case.

[0026] The term "dosage strength" refers to the weight of the active pharmaceutical ingredient per unit dosage form, such as a vial or a tablet.Synthesis method I:

[0027] each R d-11< is independently selected from C 1-6 alkyl; R d-12< is selected from halogen, preferably I or Br; the definitions of the remaining groups are consistent with those in the description of the present invention; a compound of general formula (D-1-1) and a compound of general formula (D-1-2) are subjected to an addition reaction to obtain a compound of general formula (D-1-3); the compound of general formula (D-1-3) and a compound of general formula (D-1-4) are subjected to a cyclisation reaction to obtain a compound of general formula (D-1-5); the compound of general formula (D-1-5) is subjected to a hydrolysis reaction to obtain a compound of general formula (I).

[0028] Unless stated to the contrary, the terms used in the description and claims of the present application have the following meanings.

[0029] The carbon, hydrogen, oxygen, sulphur, nitrogen, F, Cl, Br and I involved in the groups and compounds of the present invention all comprise their isotopes, and the carbon, hydrogen, oxygen, sulphur or nitrogen involved in the groups and compounds of the present invention is optionally substituted with one or more of their corresponding isotopes, wherein the isotopes of carbon comprise 12< C, 13< C and 14< C, the isotopes of hydrogen comprise protium (H), deuterium (D, also known as heavy hydrogen) and tritium (T, also known as superheavy hydrogen), the isotopes of oxygen comprise 16< O, 17< O and 18< O, the isotopes of sulphur comprise 32< S, 33< S, 34< S and 36< S, the isotopes of nitrogen comprise 14< N and 15< N, the isotopes of fluorine comprise 17< F and 19< F, the isotopes of chlorine comprise 35< Cl and 37< Cl, and the isotopes of bromine comprise 79< Br and 81< Br.

[0030] "Halogen" refers to F, Cl, Br or I.

[0031] "Halogen-substituted" refers to a substitution with F, Cl, Br, or I, including but not limited to a substitution with 1 to 10 substituents selected from F, Cl, Br, or I, or a substitution with 1 to 6 substituents selected from F, Cl, Br, or I, or a substitution with 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is referred to simply as "halo".

[0032] "Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to an alkyl group of 1 to 20 carbon atoms, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof. The definition of the "alkyl" herein is consistent with this definition. The alkyl can be monovalent, divalent, trivalent or tetravalent.

[0033] "Alkylene" refers to a substituted or unsubstituted linear or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10), and examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, etc.

[0034] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The "cycloalkyl" herein is as defined above. The cycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0035] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, or 1 to 3 heteroatoms selected from N, O or S. The selectively substituted N and S in the ring of the heterocycloalkyl can be oxidised to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom; heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring; and heterocycloalkyl can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidyl, piperidyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl or piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0036] "Alkenyl" refers to a substituted or unsubstituted linear or branched unsaturated hydrocarbon group, having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc. The definition of the alkenyl herein is consistent with this definition. The alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0037] "Alkynyl" refers to a substituted or unsubstituted linear or branched unsaturated hydrocarbon group, having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with a main chain including 2 to 10 carbon atoms, including but not limited to a main chain including 2 to 6 carbon atoms, or a main chain including 2 to 4 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc. The alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0038] "Propynyl" refers to 1-propynyl or 2-propynyl.

[0039] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0040] "Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, 4- to 12-membered bicyclic ring, or 10- to 15-membered tricyclic ring system. Carbocyclyl can be connected to an aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring is optionally a monocyclic ring, a bridged ring, or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, a benzene ring, a naphthalene ring, The "carbocyclyl" or "carbocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0041] "Heterocyclyl" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, wherein the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The selectively substituted N and S in the ring of the heterocyclyl can be oxidised to various oxidation states. Heterocyclyl can be connected to a heteroatom or a carbon atom; heterocyclyl can be connected to an aromatic ring or a non-aromatic ring; and heterocyclyl can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, The "heterocyclyl" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0042] "Spiro ring" or "spiro ring group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, or 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may optionally contain 1 to 5 heteroatoms selected from N, O or S(=O) n . The "spiro ring" or "spiro ring group" can be monovalent, divalent, trivalent or tetravalent.

[0043] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, wherein n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: The "fused ring" or "fused ring group" can be monovalent, divalent, trivalent or tetravalent.

[0044] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two rings sharing two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, wherein n is 0, 1 or 2). The number of ring atoms includes, but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane and adamantane. The "bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0045] "Carbospiro ring", "spiro ring carbocyclyl", "spirocarbocyclyl" or "carbospiro ring group" refers to a "spiro ring" with a ring system consisting only of carbon atoms.

[0046] "Carbo-fused ring", "fused ring carbocyclyl", "fused carbocyclyl" or "carbo-fused ring group" refers to a "fused ring" with a ring system consisting only of carbon atoms.

[0047] "Carbo-bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbo-bridged ring group" refers to a "bridged ring" with a ring system consisting only of carbon atoms.

[0048] "Mono-heterocyclic ring", "monocyclic heterocyclyl" or "mono-heterocyclyl" refers to "heterocyclyl" or "heterocyclic ring" with a monocyclic system.

[0049] "Fused-heterocyclic ring", "fused-heterocyclic ring group", "fused ring heterocyclyl" or "fused-heterocyclic ring group" refers to a "fused ring" containing a heteroatom.

[0050] "Spiro-heterocyclic ring", "spiro-heterocyclyl", "spiro ring heterocyclyl" or "spiro-heterocyclic ring group" refers to a "spiro ring" containing a heteroatom.

[0051] "Bridged-heterocyclic ring", "bridged-heterocyclyl", "bridged ring heterocyclyl" or "bridged-heterocyclic ring group" refers to a "bridged ring" containing a heteroatom.

[0052] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting examples include a benzene ring, a naphthalene ring, or and "aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of connection is on the aryl ring.

[0053] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, wherein n is 0, 1 or 2), wherein the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl include, but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzoimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples include and The definition of the heteroaryl herein is consistent with this definition. The heteroaryl can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of connection is on the heteroaryl ring.

[0054] "Substitution" or "substituted" refers to a substitution with 1 or more (including, but not limited to 2, 3, 4 or 5) substituents including, but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, carboxylate, -(CH 2 ) m -C(=O)-R a< , -O-(CH 2 ) m -C(=O)-R a< , -(CH2) m -C(=O)-NR b< R c< , -(CH 2 ) m S(=O) n R a< , -(CH2) m -alkenyl-R a< , OR d< or -(CH 2 ) m -alkynyl-R a< (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl, -NR b< R c< , etc., wherein R b< and R c< are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulphonyl, or trifluoromethylsulphonyl. Alternatively, R b< and R c< can form a five- or six-membered cycloalkyl or heterocyclyl. R a< and R d< are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester group, bridged ring group, spiro ring group or bicyclic ring group.

[0055] "Containing 1 to 5 heteroatoms selected from O, S and N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N.

[0056] "Substituted with 1 to X substituents selected from ..." refers to a substitution with 1, 2, 3 ... X substituents, wherein X is any integer from 1 to 10. For example, "substituted with 1 to 4 R k< " refers to a substitution with 1, 2, 3 or 4 R k< . For example, "substituted with 1 to 5 substituents selected from ..." refers to a substitution with 1, 2, 3, 4 or 5 substituents selected from ... For example, "bridged-heterocyclic ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the bridged-heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from D or F.

[0057] An X- to Y-membered ring (3 ≤ X < Y, and Y is selected from any integer between 4 and 12) includes X, X+1-, X+2-, X+3-, X+4-,...to Y-membered rings. Rings include a heterocyclic ring, a carbocyclic ring, an aromatic ring, aryl, heteroaryl, cycloalkyl, a mono-heterocyclic ring, a fused-heterocyclic ring, a spiro-heterocyclic ring, or a bridged-heterocyclic ring. For example, a "4- to 7-membered mono-heterocyclic ring" refers to a 4-, 5-, 6- or 7-membered mono-heterocyclic ring, and a "5- to 10-membered fused-heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9- or 10-membered fused-heterocyclic ring.

[0058] The term "optional" or "optionally" refers to that the events or circumstances subsequently described may but not necessarily occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, "alkyl optionally substituted with F" means that the alkyl may but not necessarily be substituted with F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.

[0059] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention, which salt maintains the biological effectiveness and characteristics of a free acid or a free base, and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.

[0060] "Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and characteristics of a compound administered.

[0061] "Co-crystal" refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between various components. The co-crystal is a multi-component crystal, which includes both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.

[0062] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.

[0063] "Stereoisomer" refers to an isomer produced as a result of different spatial arrangement of atoms in molecules, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0064] "Tautomer" refers to a functional group isomer produced by the rapid movement of an atom in two positions in a molecule, such as keto-enol isomerisation and amide-imino alcohol isomerisation.Detailed Description of Embodiments

[0065] The technical solutions of the present invention will be described in detail by the following examples, but the scope of protection of the present invention includes but is not limited thereto.

[0066] The structures of the compounds are determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in the unit of 10 -6< (ppm). NMR is determined with NMR instruments (Bruker Avance III 400 and Bruker Avance 300); the solvent for determination is deuterated dimethylsulphoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD); and the internal standard is tetramethylsilane (TMS).

[0067] MS is determined with Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0068] HPLC is determined with Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 µM).

[0069] Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate is used as a thin layer chromatography silica plate; and the silica gel plate for the thin layer chromatography (TLC) is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4 mm-0.5 mm.

[0070] Yantai Huanghai silica gel of 200-300 mesh is generally used as a carrier in column chromatography.Example 1 :

[0071] Step 1: Preparation of 1A

[0072] Compound isobutyryl chloride (7 g, 65.67 mmol) was dissolved in THF (40 mL), and the mixture was cooled to -70°C. A solution of potassium tert-butoxide in tetrahydrofuran (72 mL, 1 N) was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min, and then 100 mL of water and 50 mL of methyl tert-butyl ether were added sequentially. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.Step 2: Preparation of 1B

[0073] Compound 1A (7.77 g, 53.89 mmol) was dissolved in THF (80 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of LDA in tetrahydrofuran (80 mL, 1 N) was slowly added dropwise. After the addition, the mixture was further stirred for 30 min, warmed to 0°C and then stirred for 10 min. The mixture was cooled to -70°C, and a solution of 3-iodobenzyl bromide (16 g, 53.89 mmol) in tetrahydrofuran (20 mL) was slowly added. After the addition, the mixture was further stirred for 1 h and naturally warmed to room temperature. The reaction was quenched with 20 mL of a saturated aqueous ammonium chloride solution. 100 mL of water and 100 mL of methyl tert-butyl ether were added, and the mixture was stirred for layer separation. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V)=0 / 100-5 / 100) to obtain compound 1B (6.3 g, yield: 32%).

[0074] 1< H NMR (400 MHz, CDCl 3 ) δ 7.56-7.51 (m, 2H), 7.14-7.09 (m, 1H), 7.02 - 6.95 (m, 1H), 2.75 (s, 2H), 1.45 (s, 9H), 1.13 (s, 6H).Step 3: Preparation of 1C

[0075] Compound 1B (5.8 g, 16.10 mmol) was dissolved in THF (20 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of isopropyl magnesium chloride-lithium chloride in tetrahydrofuran (24 mL, 1 N) was slowly added dropwise. After the addition, the mixture was warmed to 0°C, stirred for 10 min and then cooled to -70°C. Diethyl oxalate (3.53 g, 24.15 mmol) was slowly added dropwise. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min. The reaction was quenched with 10 mL of a saturated aqueous ammonium chloride solution and extracted with 50 mL of methyl tert-butyl ether and 50 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-8 / 100) to obtain compound 1C (4.2 g, yield: 78%).Step 4: Preparation of 1D

[0076] Compound 1C (2.4 g, 7.18 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and water (1 mL). Malononitrile (1.90 g, 28.79 mmol) and β-alanine (0.064 g, 0.72 mmol) were added sequentially, and the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 1D (2.56 g, yield: 93%).Step 5: Preparation of 1E

[0077] Compound 1D (2.56 g, 6.69 mmol) was dissolved in THF (15 mL). Under nitrogen atmosphere, the mixture was cooled to -70°C, and a solution of methylmagnesium chloride in tetrahydrofuran (2.7 mL, 3 N) was slowly added dropwise. After the addition, the mixture was further stirred at this temperature for 10 min. The reaction was quenched with 10 ml of 1 N hydrochloric acid. 30 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 1E (2.13 g, yield: 79%).Step 6: Preparation of 1F

[0078] Compound 1E (0.54 g, 1.36 mmol), S-methylisothiourea sulphate (0.26 g, 1.36 mmol, CAS: 867-44-7) and potassium bicarbonate (0.54 g, 5.39 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 1F (0.45 g, yield: 75%).

[0079] LCMS m / z = 443.2 [M+H] +< Step 7: Preparation of 1G

[0080] Compound 1F (0.44 g, 0.99 mmol) was dissolved in THF (5 mL). m-Chloroperoxybenzoic acid (0.34 g, 1.97 mmol, wt% = 85%) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain 1G (a mixture of 1G-1 and 1G-2), which was directly used in the next step.

[0081] LCMS m / z = 457.2 [M-H] -< and LCMS m / z = 473.2 [M-H] -< Step 8: Preparation of 1H

[0082] Compound 1, 1,1,2,2-pentafluoro-4-iodobutane (2 g, 7.29 mmol), phthalimide (1.07 g, 7.29 mmol) and potassium carbonate (1.51 g, 10.94 mmol) were mixed and dissolved in DMF (20 mL). The mixture was warmed to 80°C, stirred for 3 h and cooled to room temperature. 40 mL of MTBE and 40 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 4), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 5) to obtain compound 1H (0.5 g, yield: 23%).Step 9: Preparation of 1I hydrochloride

[0083] Compound 1H (0.5 g, 1.71 mmol) was dissolved in ethanol (5 mL). Hydrazine hydrate (0.12 g, 1.98 mmol, wt% = 80%) was added, and the mixture was warmed to 78°C, stirred for 2 h and cooled to room temperature. 10 mL of ethyl acetate was added, and the mixture was filtered. The filter cake was washed with 5 mL of ethyl acetate. The filtrates were combined. A solution of hydrogen chloride in ethyl acetate (1 mL, 4 N) was added, and the mixture was concentrated under reduced pressure to obtain the hydrochloride of compound 1I, which was directly used in the next step.

[0084] LCMS m / z = 164.10 [M+H] +< Step 10: Preparation of 1J

[0085] Compound 4-chloro-2-fluoronitrobenzene (0.33 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 1J (0.43 g, yield: 72%).

[0086] LCMS m / z = 319.1 [M+H] +< Step 11: Preparation of 1K

[0087] Compound 1J (0.43 g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.64 mmol) and iron powder (0.76 g, 13.54 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 1K (0.3 g, yield: 77%).

[0088] LCMS m / z = 289.10 [M+H] +< Step 12: Preparation of 1L

[0089] Compound 1K (0.3 g, 1.04 mmol) was dissolved in DCM (5 mL), and diisopropylethylamine (0.41 g, 3.14 mmol) was added. In an ice bath, triphosgene solids (0.12 g, 0.42 mmol) were added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 1L (0.2 g, yield: 61%).

[0090] LCMS m / z = 315.0 [M+H] +< Step 13: Preparation of 1M

[0091] Compound 1L (0.2 g, 0.64 mmol), 1G (0.46 g) and potassium carbonate (0.18 g, 1.29 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 1M (55 mg, yield: 12%).

[0092] LCMS m / z = 709.70 [M+H] +< Step 14: Preparation of compound 1

[0093] Compound 1M (0.052 g, 0.073 mmol) was placed in a 50 mL single-necked flask. TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 4) to obtain compound 1 (34 mg, yield: 71%).Step 15: Compounds 1-1 and 1-2

[0094] Compound 1 (30 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: Waters 150 ap; chromatographic column: ChoralPak IC 19*250 5 um; column temperature: 35°C; mobile phase A: CO 2 , and mobile phase B: isopropanol; gradient: B 24%; back pressure: 95 bar; cycle: 3.6 min; detection wavelength: 210 nm; flow rate: 40 ml / min.

[0095] Analysis conditions: instrument: Shimadzu LC-20AD; chromatographic column: CHIRALPAK AD-H 4.6*250 mm 5 um; mobile phase A: n-hexane, and mobile phase B: ethanol; flow rate: 1 ml / min; column temperature: 35°C; detection wavelength: 210 nm; injection volume: 10 µL; run time: 20 min; isocratic elution: n-hexane: ethanol = (80 : 20).

[0096] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 1-1 (10 mg) and compound 1-2 (10 mg).Compound 1-1: retention time under analysis conditions: 5.1 min, LCMS m / z = 653.1 [M+H] +<

[0097] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, 1H), 7.53 (d, 1H), 7.28 - 7.21 (m, 1H), 7.16 - 7.03 (m, 4H), 6.78 - 6.48 (m, 2H), 4.24 (t, 2H), 2.85 - 2.65 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Compound 1-2: retention time under analysis conditions: 7.5 min, LCMS m / z = 653.1 [M+H] +<

[0098] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, 1H), 7.53 (d, 1H), 7.28 - 7.21 (m, 1H), 7.16 - 7.03 (m, 4H), 6.78 - 6.48 (m, 2H), 4.24 (t, 2H), 2.85 - 2.65 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Example 2:

[0099] Step 1: Preparation of 2A

[0100] Compound diethyl 2-(dicyanomethyl)-2-methylmalonate (CAS: 1350855-72-9) (1 g, 4.20 mmol), S-methylisothiourea sulphate (0.79 g, 4.2 mmol) and potassium bicarbonate (1.68 g, 16.78 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate was added, and the mixture was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 2A (0.9 g, yield: 76%).

[0101] LCMS m / z = 283.20 [M+H] +< Step 2: Preparation of 2B

[0102] Compound 2A (0.9 g, 3.19 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (10 mL, 7 N) was added, and the mixture was warmed to 40°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure to obtain compound 2B, which was directly used in the next step.

[0103] LCMS m / z = 254.1 [M+H] +< Step 3: Preparation of 2C

[0104] Compound 2B (0.85 g, 3.36 mmol) and Lawson's reagent (1.49 g, 3.70 mmol) were mixed and dissolved in toluene (15 mL). After the addition, the mixture was purged three times with nitrogen, warmed to 100°C and stirred overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 2C (0.52 g, yield: 57%).Step 4: Preparation of 2D

[0105] Compound methyl 4-chloro-2,2-dimethylpent-4-enoate (2 g, 11.29 mmol, CAS: 86799-85-1) was dissolved in a mixed solvent of ethanol (10 mL) and water (10 mL). In an ice bath, NBS (2.21 g, 12.42 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 1 h. The reaction was quenched by slowly adding 10 mL of a saturated aqueous sodium bicarbonate solution and extracted with 20 mL of MTBE. The organic phase was further washed with a saturated aqueous sodium bicarbonate solution (10 mL x 2), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.Step 5: Preparation of 2E

[0106] 2C (0.5 g, 1.86 mmol) and 2D (0.66 g, 2.79 mmol) were mixed and dissolved in ethanol (10 mL). The mixture was warmed to 60°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate and 20 mL of a saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred for 10 min. The organic layer was separated, washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 2E (0.55 g, yield: 73%).

[0107] LCMS m / z = 408.70 [M+H] +< Step 6: Preparation of 2F

[0108] Compound 2E (0.55 g, 1.35 mmol) was dissolved in tetrahydrofuran (5 mL), and m-chloroperoxybenzoic acid (0.47 g, 2.72 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min. 20 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain 2F (a mixture of 2F-1 and 2F-2), which was directly used in the next step.

[0109] LCMS m / z = 424.1 [M+H] +< and LCMS m / z = 440.1 [M+H] +< Step 7: Preparation of2G

[0110] Compound 1L (0.12 g, 0.38 mmol), 2F (0.19 g) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C, stirred for 16 h and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3) to obtain compound 2G (54 mg, yield: 21%).

[0111] LCMS m / z = 674.1 [M+H] +< Step 8: Preparation of compound 2

[0112] Compound 2G (0.054 g, 0.080 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.019 g, 0.79 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding 1 N hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 2 (31 mg).

[0113] LCMS m / z = 660.0 [M+H] +<

[0114] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 7.81 (d, 1H), 7.52 (d, 1H), 7.25 (s, 1H), 7.13 (dd, 1H), 7.09 - 6.96 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.81 - 2.65 (m, 2H), 1.81 (s, 3H), 1.14 - 1.04 (m, 6H).Preparation of compound 2-1 and compound 2-2:

[0115]

[0116] The trifluoroacetate of compound 2 (31 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 52 ml / min.

[0117] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution: mobile phase B: 10%-40%; time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0118] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 2-1 (10 mg) and compound 2-2 (15 mg).Compound 2-1: retention time under analysis conditions: 2.3 min, LCMS m / z = 660.0 [M+H] +< Compound 2-2: retention time under analysis conditions: 2.7 min, LCMS m / z = 660.0 [M+H] +< Example 3:

[0119] Step 1: Preparation of3A

[0120] Pyridazine (3 g, 37.50 mmol) was dissolved in chloroform (60 mL). Trifluoromethanesulphonic anhydride (12.59 g, 44.63 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. Trimethylsilyl cyanide (15.81 g, 159.26 mmol) was added, and the mixture was warmed to 60°C, reacted for 3 h and cooled. Then, N-methyl morpholine (4.93 g, 48.75 mmol) was added, and the mixture was warmed to 60°C again, reacted overnight and cooled to room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted twice with DCM. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 13) to obtain compound 3A (2.5 g, yield: 63%).

[0121] LCMS m / z = 106.20 [M+H] +< Step 2: Preparation of 3B hydrochloride

[0122] Compound 3A (2 g, 19.03 mmol) was dissolved in methanol (10 mL). 10 mL of 6 N hydrochloric acid and palladium on carbon (2.03 g, 1.90 mmol) were added, and the mixture was purged three times with hydrogen and reacted overnight under hydrogen atmosphere. The reaction solution was filtered over celite and washed 3 times with methanol. The filtrate was concentrated under reduced pressure to obtain compound 3B hydrochloride, which was directly used in the next step.Step 3: Preparation of3C

[0123] Compound 3B hydrochloride (1.1 g, 7.52 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.73 g, 9.02 mmol) were dissolved in DMF (20 mL). HATU (5.72 g, 15.04 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (2.92 g, 22.56 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 10) to obtain compound 3C (700 mg, yield: 32%).Step 4: Preparation of 3D

[0124] Compound 3C (700 mg, 2.47 mmol) was dissolved in DCE (100 mL). Phosphorus oxychloride (1.31 mL, 14.35 mmol) was added, and the mixture was warmed to reflux, reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 3D (350 mg, yield: 53%).

[0125] LCMS m / z = 266.30 [M+H] +< Step 5: Preparation of3E

[0126] Compound 3D (350 mg, 1.32 mmol) was dissolved in DCM (10 mL). NBS (246.68 mg, 1.39 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-50 / 100) to obtain compound 3E (430 mg, yield: 94%).

[0127] LCMS m / z = 344.30 [M+H] +< Step 6: Preparation of 3F

[0128] Compound 3E (400 mg, 1.16 mmol) and zinc cyanide (272.46 mg, 2.32 mmol) were added to a 50 mL single-necked flask, and then zinc powder (151.75 mg, 2.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene (385.85 mg, 0.70 mmol), tris(dibenzylidene-BASE acetone)dipalladium (318.67 mg, 0.35 mmol) and N,N-dimethylacetamide (10 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 50 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain compound 3F (320 mg, yield: 95%).

[0129] LCMS m / z = 291.1 [M+H] +< Step 7: Preparation of3G

[0130] In an ice bath, ammonium chloride (275.47 mg, 5.15 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (2.58 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 3F (300 mg, 1.03 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 3G (190 mg, yield: 60%).

[0131] LCMS m / z = 308.50 [M+H] +< Step 8: Preparation of3H

[0132] Diethyl 2-bromo-2-methylmalonate (20.00 g, 79.02 mmol) and malononitrile (5.22 g, 79.02 mmol) were dissolved in tetrahydrofuran (120 mL). In an ice bath, potassium tert-butoxide (8.87 g, 79.02 mmol) was added in portions. After the addition, the mixture was warmed to 85°C and stirred for 16 h. The reaction solution was cooled to room temperature and subjected to suction filtration to remove the solid. The filter cake was washed with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 3H (4.94 g, yield: 26%).

[0133] LCMS m / z = 239.1 [M+H] +< Step 9: Preparation of 3I

[0134] Compound 3G (190 mg, 0.62 mmol), 3H (177.25 mg, 0.74 mmol) and potassium bicarbonate (124.15 mg, 1.24 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 3I (250 mg, yield: 80%).Step 10: Preparation of 3J

[0135] Compound 3I (250 mg, 0.50 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (5 mL, 7 N) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 3J (230 mg, yield: 97%).

[0136] LCMS m / z = 471.1 [M+H] +< Step 11: Preparation of 3K

[0137] Compound 3J (230 mg, 0.49 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (237.83 mg, 0.59 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 3K (200 mg, yield: 83%).

[0138] LCMS m / z = 487.0 [M+H] +< Step 12: Preparation of3L

[0139] Compound 3K (200 mg, 0.41 mmol) was dissolved in ethanol (5 mL). 2D (145.81 mg, 0.61 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 3L (200 mg, yield: 78%).

[0140] LCMS m / z = 625.1 [M+H] +< Step 13: Preparation of compound 3

[0141] Compound 3L (200 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain compound 3 (100 mg, yield: 51%)

[0142] LCMS m / z = 611.2 [M+H] +<

[0143] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.38 - 11.89 (m, 1H), 11.33 (s, 1H), 9.00 (dd, 1H), 8.45 (dd, 1H), 7.24 (s, 1H), 6.99 (dd, 1H), 6.78 (br.s, 1H), 3.42-3.34 (m, 2H), 2.96 - 2.76 (m, 4H), 1.79 (s, 3H), 1.11 (s, 6H).Preparation of compound 3-1 and compound 3-2:

[0144]

[0145] Compound 3 (100 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 30%; c. flow rate: 54 mL / min.

[0146] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 3-1 (35 mg) and compound 3-2 (35 mg).Compound 3-1: retention time under chiral preparative conditions: 3.33 min, LCMS m / z = 611.2 [M+1] +< Compound 3-2: retention time under chiral preparative conditions: 8.60 min, LCMS m / z = 611.2 [M+1] +< Example 4:

[0147] Step 1: Preparation of 4A

[0148] Compound methyl 2-bromo-5-chlorobenzoate (2 g, 8.02 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.69 g, 8.82 mmol) were dissolved in THF (40 mL). At -78°C, sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (60 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 4A (1.6 g, yield: 54%).Step 2: Preparation of 4B

[0149] Compound 4A (1.6 g, 4.38 mmol) was dissolved in methanol (10 mL). Aminoguanidine hydrochloride (0.72 g, 6.54 mmol) and boron trifluoride diethyl etherate (1.1 mL, 8.91 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 4B, which was directly used in the next step.

[0150] LCMS m / z = 421.0 [M+H] +< Step 3: Preparation of 4C

[0151] Compound 4B (1.6 g, 3.80 mmol), 3H (1.81 g, 7.6 mmol) and potassium tert-butoxide (0.43 g, 3.8 mmol) were mixed and dissolved in tert-butanol (15 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 4C (550 mg, yield: 23%).

[0152] LCMS m / z = 613.0 [M+H] +< Step 4: Preparation of 4D

[0153] Compound 4C (550 mg, 0.90 mmol) was dissolved in DMF (10 mL). N,N-dimethylethylenediamine (119 mg, 1.35 mmol) and cuprous iodide (34.28 mg, 0.18 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 4D (170 mg, yield: 35%).

[0154] LCMS m / z = 533.30 [M+H] +< Step 5: Preparation of 4E

[0155] Compound 4D (170 mg, 0.32 mmol) was dissolved in methanol (3 mL). A solution of ammonia in methanol (3 mL, 7 M) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 4E (160 mg).

[0156] LCMS m / z = 504.1 [M+H] +< Step 6: Preparation of 4F

[0157] Compound 4E (160 mg, 0.32 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (155.32 mg, 0.38 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 4F (160 mg, yield: 96%).

[0158] LCMS m / z = 520.50 [M+H] +< Step 7: Preparation of 4G

[0159] Compound 4F (160 mg, 0.31 mmol) was dissolved in ethanol (5 mL). 2D (110.25 mg, 0.46 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 4G (110 mg, yield: 53%).Step 8: Preparation of compound 4

[0160] Compound 4G (110 mg, 0.17 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (71.33 mg, 1.7 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain the trifluoroacetate of compound 4 (90 mg).

[0161] LCMS m / z = 644.0 [M+H] +<

[0162] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.85 (d, 1H), 8.10 (d, 1H), 7.55 (dd, 1H), 7.24 (s, 1H), 7.21 - 7.01 (m, 2H), 3.37 - 3.24 (m, 2H), 2.93 (s, 2H), 2.87 - 2.70 (m, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 4-1 and compound 4-2:

[0163]

[0164] Compound 4 (90 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 25%; c. flow rate: 50 mL / min.

[0165] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 4-1 (20 mg) and compound 4-2 (20 mg).Compound 4-1: retention time under chiral preparative conditions: 3.80 min, LCMS m / z = 644.1 [M+1] +< Compound 4-2: retention time under chiral preparative conditions: 10.10 min, LCMS m / z = 644.0 [M+1] +< Example 5:

[0166]

[0167] With reference to the synthesis for Example 1 and Example 4 , the trifluoroacetate of compound 5 (15 mg) was obtained.

[0168] LCMS m / z = 604.3[M+H] +<

[0169] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 9.19 (dd, 1H), 8.67 (dd, 1H), 7.58 (dd, 1H), 7.25 (t, 1H), 7.19 - 7.03 (m, 3H), 6.99 - 6.39 (m, 2H), 3.44 - 3.33 (m, 2H), 3.01 - 2.84 (m, 2H), 2.84 - 2.69 (m, 2H), 1.79 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H).Example 6:

[0170] Step 1: Preparation of 6A

[0171] 5-Chloro-2-bromo-3-nitropyridine (5.00 g, 21.08 mmol) and tert-butyl cyanoacetate (4.32 g, 30.57 mmol) were dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (7.87 g, 56.92 mmol) was added. After the addition, the mixture was warmed to 100°C and stirred for 1 h. The reaction solution was cooled to room temperature, and water was added to dissolve potassium carbonate. Then, the mixture was adjusted to pH = 2 with dilute hydrochloric acid, with light-yellow solids precipitated. The resulting mixture was subjected to suction filtration. The filter cake was washed 3 times with water, redissolved in dichloromethane, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 6A (3.04 g, yield: 48%).Step 2: Preparation of 6B

[0172] In a 100 mL reaction flask, 26 mL of concentrated hydrochloric acid was added to 20 mL of water. 6A (3.04 g, 10.21 mmol) was added, forming a suspension. Then, glacial acetic acid (24 mL) was added. After the addition, the mixture was warmed to 80°C and stirred for 30 min. The reaction solution was cooled to room temperature. The reaction was quenched with water. 500 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic phase was washed 3 times with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 6B (1.4 g, yield: 69%).

[0173] LCMS m / z = 198.1[M+H] +< Step 3: Preparation of 6C

[0174] Compound 6B (1.20 g, 6.07 mmol) was dissolved in tetrahydrofuran (30 mL). Zinc powder (1.99 g, 30.35 mmol) was added, and then an aqueous ammonium chloride solution (1.62 g, 30.35 mmol, 5 mL) was added dropwise. At room temperature, the mixture was stirred and reacted for 0.5 h. To the reaction solution was added 1 mL of aqueous ammonia and 10 mL of water. The mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 6C (0.91 g, yield: 89%).

[0175] LCMS m / z = 168.1 [M+H] +< Step 4: Preparation of 6D

[0176] Compound 6C (0.61 g, 3.64 mmol) was dissolved in concentrated hydrochloric acid (3 mL) and water (15 mL). In an ice bath, sodium nitrite (0.41 g, 5.93 mmol) was added, and the mixture was stirred at room temperature for 16 h, with yellow solids precipitated. The resulting mixture was subjected to suction filtration to obtain solids, which were dissolved in glacial acetic acid (6 mL). The mixture was warmed to 100°C, reacted for 2 h and concentrated under reduced pressure. The residue was directly purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 6D (0.24 g, yield: 37%).

[0177] LCMS m / z = 179.10 [M+H] +< Step 5: Preparation of 6E

[0178] Compound 6D (0.34 g, 1.89 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (1.14 g, 4.16 mmol) were dissolved in acetonitrile (15 mL). Potassium carbonate (1.31 g, 9.45 mmol) was added. The mixture was warmed to 100°C, stirred and reacted for 16 h. The reaction solution was cooled to room temperature and subjected to suction filtration to remove solids. The filter cake was washed 3 times with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 5 / 1) to obtain compound 6E (0.44 g, yield: 71%).

[0179] LCMS m / z = 325.00 [M+H] +< Step 6: Preparation of 6F

[0180] In an ice bath, ammonium chloride (0.36 g, 6.80 mmol) was added to a 500 mL single-necked flask. Toluene (30 mL) was added, and then trimethylaluminium (3.9 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 6E (0.44 g, 1.36 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred for 6 h and cooled to room temperature. In an ice bath, silica gel and 100 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 6F (0.46 g, yield: 99%).

[0181] LCMS m / z = 342.0 [M+H] +< Step 7: Preparation of compound 6F-0

[0182] At -78°C, lithium diisopropylamide (60 mL, 2 M in THF) was added dropwise to a solution of methyl isobutyrate (10.18 g, 99.72 mmol) in tetrahydrofuran (500 mL). At -78°C, the mixture was stirred for 0.5 h, and then 3-iodobenzyl bromide (29.6 g, 99.69 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (400 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 10) to obtain compound 6F-0 (18 g, yield: 57%).

[0183] 1< H NMR (400 MHz, CDCl 3 ) δ 7.57 - 7.44 (m, 2H), 7.10 - 7.03 (m, 1H), 6.99 (t, 1H), 3.66 (s, 3H), 2.78 (s, 2H), 1.18 (s, 6H).Step 8: Preparation of compound 6F-1

[0184] At -78°C, an isopropyl magnesium chloride-lithium chloride complex (35 mL, 1.3 M in THF) was added dropwise to a solution of compound 6F-0 (10 g, 31.4 mmol) in tetrahydrofuran (200 mL), the mixture was stirred for 30 min, and then ethyl 3,3-dicyano-2-methylacrylate (synthesised with reference to synthesis, 1974: 9,669) (5.16 g, 31.43 mmol) was slowly added. After the addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL×2). The organic phases were combined, dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 10) to obtain compound 6F-1 (5 g, yield: 45%).Step 9: Preparation of 6G

[0185] Compound 6F (0.10 g, 0.29 mmol), 6F-1 (0.10 g, 0.29 mmol) and potassium bicarbonate (0.09 g, 0.87 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 6G (0.16 g).

[0186] LCMS m / z = 652.2 [M+H] +< Step 10: Preparation of compound 6

[0187] Compound 6G (0.16 g, 0.25 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.10 g, 2.50 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 6 (0.14 g, yield: 87%).

[0188] LCMS m / z = 638.1 [M+H] +<

[0189] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.68 - 8.57 (m, 2H), 7.25 (t, 1H), 7.16 - 7.04 (m, 3H), 6.46 (s, 2H), 4.86 (t, 2H), 3.05 - 2.88 (m, 2H), 2.84 - 2.70 (m, 2H), 1.79 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Preparation of compound 6-1 and compound 6-2:

[0190]

[0191] Compound 6 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm*250 mm); The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 , and mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 30%; c. flow rate: 54 ml / min.

[0192] Analytical method: 1. instrument: UPC2; chromatographic column: IG (3 mm×50 mm); 2. the sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); b. gradient elution, mobile phase B: 10%-40%, time: 5 min; c. flow rate: 1.5 ml / min.

[0193] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 6-1 (55 mg) and compound 6-2 (40 mg).Compound 6-1: retention time under analysis conditions: 2.824 min, LCMS m / z = 638.1 [M+H] +< Compound 6-2: retention time under analysis conditions: 4.098 min, LCMS m / z = 638.1 [M+H] +< Example 7:

[0194]

[0195] With reference to the synthesis for Example 6, compound 7 (0.073 g) was obtained.

[0196] LCMS m / z = 622.2 [M+H] +<

[0197] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.12 (s, 1H), 9.20 (d, 1H), 8.28 (d, 1H), 7.33 - 7.20 (m, 1H), 7.14 - 7.03 (m, 3H), 6.52 - 6.30 (m, 2H), 5.00 (t, 2H), 3.10 - 2.93 (m, 2H), 2.86 - 2.68 (m, 2H), 1.80 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Example 8:

[0198] Step 1: Preparation of 8A

[0199] Compound 21D (0.5 g, 1.44 mmol), S-methylisothiourea sulphate (0.27 g, 1.44 mmol) and potassium bicarbonate (0.58 g, 5.76 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was slurried with 15 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 4) to obtain compound 8A (0.4 g).

[0200] LCMS m / z = 392.1 [M+H] +< Step 2: Preparation of8B

[0201] Compound 8A (0.52 g, 1.33 mmol) was dissolved in THF (5 mL), and m-chloroperoxybenzoic acid (0.46 g, 2.66 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain compound 8B, which was directly used in the next step.Step 3: Preparation of8C

[0202] Compound 1L (0.12 g, 0.38 mmol), 8B (0.23 g, 0.57 mmol) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 8C (54 mg, yield: 21%).

[0203] LCMS m / z = 658.2 [M+H] +< Step 4: Preparation of compound 8

[0204] Compound 8C (0.054 g, 0.082 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.020 g, 0.83 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous hydrochloric acid solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 8 (30 mg, yield: 56%).

[0205] LCMS m / z = 644.2 [M+H] +<

[0206] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 7.80 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.15-7.10 (m, 1H), 6.91-6.67 (m, 2H), 4.23 (t, 2H), 2.83 - 2.62 (m, 4H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 9:

[0207] Step 1: Preparation of9A

[0208] Compound 1I hydrochloride (0.5 g, 2.51 mmol) and 2-fluoro-3-nitropyridine (0.36 g, 2.51 mmol) were dissolved in DMSO (5 mL). DIPEA (0.97 g, 7.53 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 9A (0.62 g, yield: 86%).

[0209] LCMS m / z = 286.30 [M+H] +< Step 2: Preparation of9B

[0210] Compound 9A (0.62 g, 2.17 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.16 g, 21.69 mmol) and iron powder (1.21 g, 21.66 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 9B (0.48 g, yield: 86%).Step 3: Preparation of9C

[0211] Compound 9B (0.48 g, 1.88 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.46 g, 2.84 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 9C (0.32 g, yield: 60%).

[0212] LCMS m / z = 282.1[M+H] +< Step 4: Preparation of9D

[0213] Compound 9C (0.12 g, 0.43 mmol), 1G (0.30 g) and potassium carbonate (0.12 g, 0.87 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 9D (0.2 g, yield: 68%).

[0214] LCMS m / z = 676.3 [M+H] +< Step 5: Preparation of compound 9

[0215] Compound 9D (0.20 g, 0.30 mmol) was placed in a 50 mL single-necked flask. Trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 5). The resulting crude was further purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 9 (80 mg, yield: 43%).

[0216] LCMS m / z = 620.3[M+H] +<

[0217] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.90 (m, 1H), 11.22 (s, 1H), 8.29-8.23 (m, 1H), 8.15-8.09 (m, 1H), 7.28-7.21 (m, 1H), 7.18 - 7.03 (m, 4H), 6.80-6.44 (m, 2H), 4.25 (t, 2H), 2.92 - 2.70 (m, 4H), 1.78 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H).Preparation of compound 9-1 and compound 9-2:

[0218]

[0219] Compound 9 (80 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 25%; flow rate: 44 ml / min.

[0220] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0221] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 9-1 (25 mg) and compound 9-2 (35 mg).Compound 9-1: retention time under analysis conditions: 1.9 min, LCMS m / z = 620.2 [M+H] +< Compound 9-2: retention time under analysis conditions: 2.2 min, LCMS m / z = 620.2 [M+H] +< Example 10:

[0222]

[0223] With reference to the synthesis for Example 9 and Example 2, the trifluoroacetate of compound 10 (15 mg) was obtained.

[0224] LCMS m / z = 627.2 [M+H] +<

[0225] 1< H NMR (400 MHz, DMSO-d 6 ) 11.57 (s, 1H), 8.28-8.22 (m, 1H), 8.15-8.09 (m, 1H), 7.26 (s, 1H), 7.18-7.12 (m, 1H), 7.12-7.02 (m, 2H), 4.24 (t, 2H), 2.93 (s, 2H), 2.89-2.73 (m, 2H), 1.81 (s, 3H), 1.14-1.05(m, 6H).Example 11:

[0226] Step 1: Preparation of 11A

[0227] Compound 1I hydrochloride (0.5 g, 2.51 mmol) and 2,4-difluoronitrobenzene (0.40 g, 2.51 mmol) were dissolved in DMSO (5 mL). DIPEA (0.98 g, 7.58 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 11A (0.62 g, yield: 82%).Step 2: Preparation of 11B

[0228] Compound 11A (0.62 g, 2.05 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.10 g, 20.56 mmol) and iron powder (1.14 g, 20.42 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 11B (0.48 g, yield: 86%).

[0229] LCMS m / z = 273.30 [M+H] +< Step 3: Preparation of 11C

[0230] Compound 11B (0.48 g, 1.76 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.43 g, 2.66 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 11C (0.3 g, yield: 57%).

[0231] LCMS m / z = 299.1 [M+H] +< Step 4: Preparation of 11D

[0232] Compound 11C (0.14 g, 0.47 mmol), 8B (0.29 g, 0.70 mmol) and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 11D (0.07 g, yield: 23%).

[0233] LCMS m / z = 642.3 [M+H] +< Step 5: Preparation of compound 11

[0234] Compound 11D (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.026 g, 1.09 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 11 (20 mg, yield: 29%).

[0235] LCMS m / z = 628.2 [M+H] +<

[0236] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.49 (s, 1H), 7.87-7.79 (m, 1H), 7.75 (s, 1H), 7.39-7.30 (m, 1H), 6.98-6.87 (m, 1H), 6.87-6.60 (m, 2H), 4.22 (t, 2H), 2.80 - 2.60 (m, 4H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 12:

[0237] Step 1: Preparation of 12A

[0238] Compound 2-chloro-3-nitro-5-fluoropyridine (0.33 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 12A (0.42 g, yield: 74%).Step 2: Preparation of 12B

[0239] Compound 12A (0.4 g, 1.32 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 12B (0.3 g, yield: 83%).Step 3: Preparation of 12C

[0240] Compound 12B (0.3 g, 1.1 mmol) was dissolved in THF (5 mL). In an ice bath, N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 12C (0.2 g, yield: 61%).

[0241] LCMS m / z = 300.1[M+H] +< Step 4: Preparation of 12D

[0242] Compound 2E (0.3 g, 0.74 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.8 mL). Lithium hydroxide hydrate (0.17 g, 7.16 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 12D (0.25 g, yield: 86%).Step 5: Preparation of 12E

[0243] Compound 12D (0.25 g, 0.64 mmol) was dissolved in tetrahydrofuran (7 mL), and m-chloroperoxybenzoic acid (0.33 g, 1.92 mmol) was added at room temperature. After the addition, the mixture was further stirred for 2 h. 10 mL of a saturated aqueous sodium thiosulphate solution was added, and the mixture was stirred for 20 min. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min. 20 mL of ethyl acetate was added, and the mixture was stirred for layer separation. The organic layer was washed with 10 mL of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulphate, filtered and concentrated to obtain compound 12E, which was directly used in the next step.Step 6: Preparation of compound 12

[0244] Compound 12C (0.05 g, 0.17 mmol), 12E (0.072 g, 0.17 mmol) and potassium carbonate (0.047 g, 0.34 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 12 (10 mg, yield: 9%).

[0245] LCMS m / z = 645.2[M+H] +<

[0246] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.35 (dd, 1H), 8.17 - 8.13 (m, 1H), 7.26 (s, 1H), 7.22-7.02 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.72 (m, 2H), 1.81 (s, 3H), 1.16-1.04 (m, 6H).Preparation of compound 12-1 and compound 12-2:

[0247]

[0248] Compound 12 (110 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 12%; c. flow rate: 40 ml / min.

[0249] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 12-1 (50 mg) and compound 12-2 (50 mg).Compound 12-1: retention time under chiral preparative conditions: 9.62 min, LCMS m / z = 645.2 [M+H] +<

[0250] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.35 (dd, 1H), 8.18 - 8.10 (m, 1H), 7.26 (s, 1H), 7.23 - 7.01 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.71 (m, 2H), 1.80 (s, 3H), 1.16 - 1.03 (m, 6H).Compound 12-2: retention time under chiral preparative conditions: 13.68 min, LCMS m / z = 645.2 [M+H] +<

[0251] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 8.35 (dd, 1H), 8.19 - 8.12 (m, 1H), 7.26 (s, 1H), 7.22 - 7.05 (m, 2H), 4.22 (t, 2H), 2.93 (s, 2H), 2.88 - 2.71 (m, 2H), 1.81 (s, 3H), 1.16 - 1.02 (m, 6H).Example 13:

[0252] Step 1: Preparation of 13B

[0253] Compound 2-chloro-3-nitro-5-fluoropyridine (0.3 g, 1.87 mmol) and compound 13A (0.21 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 13B (0.4 g, yield: 84%).Step 2: Preparation of 13C

[0254] Compound 13B (0.4 g, 1.58 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.64 mmol) and iron powder (0.76 g, 13.54 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 13C (0.3 g, yield: 85%).Step 3: Preparation of 13D

[0255] Compound 13C (0.3 g, 1.34 mmol) was dissolved in THF (15 mL). In an ice bath, N,N'-carbonyldiimidazole (0.65 g, 4.01 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 13D (0.24 g, yield: 72%).

[0256] LCMS m / z = 250.2[M+H] +< Step 4: Preparation of compound 13

[0257] Compound 13D (40 mg, 0.16 mmol), 12E (68 mg, 0.16 mmol) and potassium carbonate (44 mg, 0.32 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 13 (20 mg, yield: 21%).

[0258] LCMS m / z = 595.3[M+H] +<

[0259] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.28 (dd, 1H), 8.13 - 8.07 (m, 1H), 7.26 (s, 1H), 7.22-7.01 (m, 2H), 3.74 (d, 2H), 2.93 (s, 2H), 1.97- 1.86 (m, 1H), 1.81 (s, 3H), 1.74 - 1.52 (m, 5H), 1.26 - 0.92 (m, 11H).Example 14:

[0260] Step 1: Preparation of 14A

[0261] Compound 2,3-difluoronitrobenzene (0.3 g, 1.87 mmol) and compound 1I hydrochloride (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 14A (0.4 g, yield: 71%).Step 2: Preparation of 14B

[0262] Compound 14A (0.4 g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.7 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 14B (0.3 g, yield: 84%).Step 3: Preparation of 14C

[0263] Compound 14B (0.3 g, 1.1 mmol) was dissolved in THF (10 mL). In an ice bath, N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 14C (0.2 g, yield: 61%).

[0264] LCMS m / z = 299.1[M+H] +< Step 4: Preparation of 14D

[0265] Compound 14C (0.1 g, 0.34 mmol), 2F (0.15 g) and potassium carbonate (0.094 g, 0.68 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 14D (20 mg, yield: 9%).Step 5: Preparation of trifluoroacetate of compound 14

[0266] Compound 14D (20 mg, 0.03 mmol) was dissolved in a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL). Lithium hydroxide hydrate (12.6 mg, 0.3 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain the trifluoroacetate of compound 14 (10 mg)

[0267] LCMS m / z = 644.2[M+H] +<

[0268] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 7.64-7.56 (m, 1H), 7.26 (s, 1H), 7.14-7.04 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.82-2.62 (m, 2H), 1.82 (s, 3H), 1.15-1.05 (m, 6H).Preparation of compound 14-1 and compound 14-2

[0269] Compound 14 (100 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 20%; c. flow rate: 40 ml / min.

[0270] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 14-1 (40 mg) and compound 14-2 (40 mg). Compound 14-1: retention time under chiral preparative conditions: 5.40 min, LCMS m / z = 644.2 [M+H] +<

[0271] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 7.64 - 7.56 (m, 1H), 7.26 (s, 1H), 7.16 - 6.99 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.81-2.64 (m, 2H), 1.82 (s, 3H), 1.15 - 1.05 (m, 6H).Compound 14-2: retention time under chiral preparative conditions: 8.53 min, LCMS m / z = 644.2 [M+H] +<

[0272] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 7.64 - 7.55 (m, 1H), 7.26 (s, 1H), 7.20 - 6.95 (m, 4H), 4.29 (t, 2H), 2.93 (s, 2H), 2.82 - 2.62 (m, 2H), 1.82 (s, 3H), 1.18 - 1.01 (m, 6H).Example 15:

[0273] Step 1: Preparation of 15A

[0274] Compound 2,3-difluoronitrobenzene (0.23 g, 1.87 mmol) and compound 15A (0.3 g, 1.87 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (0.71 g, 5.49 mmol) was added, and the mixture was warmed to 60°C, stirred for 4 h and cooled to room temperature. 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-1 / 10) to obtain compound 15B (0.4 g, yield: 81%).Step 2: Preparation of 15C

[0275] Compound 15B (0.4 g, 1.51 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.81 g, 15.1 mmol) and iron powder (0.84 g, 15.1 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10-3 / 10) to obtain compound 15C (0.3 g, yield: 85%).Step 3: Preparation of 15D

[0276] Compound 15C (0.3 g, 1.28 mmol) was dissolved in THF (10 mL). In an ice bath, N,N'-carbonyldiimidazole (0.62 g, 3.84 mmol) was added in portions. After the addition, the mixture was naturally warmed to room temperature and stirred for 2 h. 10 mL of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 10 min and extracted with 20 mL of dichloromethane. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10-1 / 2) to obtain compound 15D (0.2 g, yield: 60%).

[0277] LCMS m / z = 261.2[M+H] +< Step 4: Preparation of 15E

[0278] Compound 15D (0.15 g, 0.58 mmol), 2F (0.25 g) and potassium carbonate (0.16 g, 1.16 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C and stirred for 16 h, further warmed to 120°C and stirred for 24 h, and cooled to room temperature. 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reversed-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 15E (0.1 g, yield: 28%).Step 5: Preparation of compound 15

[0279] Compound 15E (100 mg, 0.16 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL). Lithium hydroxide hydrate (38 mg, 1.6 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50). The resulting product was treated with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and concentrated under reduced pressure. An appropriate amount of water and acetonitrile was added, and the mixture was subjected to lyophilisation to obtain the trifluoroacetate of compound 15 (20 mg)

[0280] LCMS m / z = 606.2[M+H] +<

[0281] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 7.61 (d, 1H), 7.40-7.31 (m, 1H), 7.29 - 6.91 (m, 8H), 5.23 (s, 2H), 2.93 (s, 2H), 1.82 (s, 3H), 1.10 (s, 6H).Preparation of compound 15-1 and compound 15-2:

[0282] Compound 15 (200 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0283] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 15-1 (70 mg) and compound 15-2 (80 mg).Compound 15-1: retention time under chiral preparative conditions: 7.38 min, LCMS m / z = 606.2 [M+1] +< Compound 15-2: retention time under chiral preparative conditions: 11.93 min, LCMS m / z = 606.2 [M+1] +< Example 16:

[0284]

[0285] With reference to the synthesis for Example 8, compound 16 (20 mg) was obtained.

[0286] LCMS m / z = 628.2[M+H] +<

[0287] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 7.75 (s, 1H), 7.63 - 7.56 (m, 1H), 7.13-7.05 (m, 2H), 6.96-6.68 (m, 2H), 4.29 (t, 2H), 2.82 - 2.60 (m, 4H), 1.82 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H).Example 17:

[0288] Step 1: Preparation of 17A

[0289] Compound methyl 2-bromo-5-fluorobenzoate (5 g, 21.43 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (5.66 g, 23.57 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (32.1 mL, 2 M, 64.28 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (160 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 17A (2.9 g, yield: 38%).Step 2: Preparation of 17B

[0290] Compound 17A (2 g, 5.73 mmol) was dissolved in methanol (20 mL). Aminoguanidine hydrochloride (0.95 g, 8.59 mmol) and boron trifluoride diethyl etherate (1.41 mL, 11.46 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 17B, which was directly used in the next step.

[0291] LCMS m / z = 405.10 [M+H] +< Step 3: Preparation of 17C

[0292] Compound 17B (1 g, 2.47 mmol), 3H (1.18 g, 4.94 mmol) and potassium tert-butoxide (0.28 g, 2.47 mmol) were mixed and dissolved in tert-butanol (10 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 17C (320 mg, yield: 21%).Step 4: Preparation of 17D

[0293] Compound 17C (300 mg, 0.50 mmol) was dissolved in DMF (5 mL). N,N-dimethylethylenediamine (66.11 mg, 0.75 mmol) and cuprous iodide (19.04 mg, 0.10 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 17D (190 mg, yield: 73%).Step 5: Preparation of 17E

[0294] Compound 17D (190 mg, 0.37 mmol) was dissolved in methanol (3 mL). A solution of ammonia in methanol (3 mL, 7 M) was added, and the mixture was reacted overnight at 40°C and concentrated under reduced pressure to obtain compound 17E (180 mg).

[0295] LCMS m / z = 488.30 [M+H] +< Step 6: Preparation of 17F

[0296] Compound 17E (180 mg, 0.37 mmol) was dissolved in toluene (5 mL). Lawesson's Reagent (224.48 mg, 0.55 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 17F (170 mg, yield: 91%).

[0297] LCMS m / z = 504.20 [M+H] +< Step 7: Preparation of17G

[0298] Compound 17F (170 mg, 0.34 mmol) was dissolved in ethanol (5 mL). 2D (110.25 mg, 0.46 mmol) was added. After the addition, the mixture was warmed to 80°C, stirred overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-5 / 1) to obtain compound 17G (150 mg, yield: 68%).

[0299] LCMS m / z = 642.40 [M+H] +< Step 8: Preparation of compound 17

[0300] Compound 17G (150 mg, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (96.51 mg, 2.3 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with the solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude was further subjected to preparative HPLC (instrument: Waters AutoP (preparative liquid phase); chromatographic column: SunFire@ Prep C18 (19 mm×250 mm); composition of mobile phase: Mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonium acetate) to obtain compound 17 (65 mg, yield: 45%).

[0301] LCMS m / z = 628.20 [M+H] +<

[0302] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.26-12.02 (m, 1H), 11.52 (s, 1H), 8.87 (dd,1H), 7.81 (dd, 1H), 7.47-7.39 (m, 1H), 7.25 (s, 1H), 7.20-7.00 (m, 2H), 3.30 - 3.24 (m, 2H), 2.93 (s, 2H), 2.88 - 2.66 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 17-1 and compound 17-2:

[0303] Compound 17 (60 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 30%; c. flow rate: 45 mL / min.

[0304] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 17-1 (15 mg) and compound 17-2 (20 mg). Compound 17-1: retention time under chiral preparative conditions: 3.33 min, LCMS m / z = 628.0 [M+1] +<

[0305] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.24 - 12.11 (m, 1H), 11.52 (s, 1H), 8.87 (dd, 1H), 7.81 (dd, 1H), 7.49 - 7.38 (m, 1H), 7.25 (s, 1H), 7.21 - 7.01 (m, 2H), 3.30 - 3.24 (m, 2H), 2.93 (s, 2H), 2.87 - 2.69 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Compound 17-2: retention time under chiral preparative conditions: 7.02 min, LCMS m / z = 628.0 [M+1] +< Example 18:

[0306]

[0307] With reference to the synthesis for Example 3 and Example 6, compound 18 (100 mg) was obtained.

[0308] LCMS m / z = 604.2 [M+H] +<

[0309] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.55-11.75 (m, 1H), 11.14 (s, 1H), 8.97 (d, 1H), 8.50 (s, 1H), 7.28-7.21 (m, 1H), 7.18 - 7.00 (m, 4H), 6.72-6.35 (m, 2H), 3.46 - 3.35 (m, 2H), 2.95-2.69 (m, 4H), 1.79 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H).Example 19:

[0310] Step 1: Preparation of 19A

[0311] Compound 3B hydrochloride (2.83 g, 19.41 mmol) and o-fluorophenylacetic acid (2 g, 12.94 mmol) were dissolved in DMF (20 mL). HATU (7.38 g, 19.41 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (5.02 g, 38.81 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 10) to obtain compound 19A (420 mg, yield: 13%).

[0312] LCMS m / z = 246.2 [M+H] +< Step 2: Preparation of 19B

[0313] Compound 19A (420 mg, 1.71 mmol) was dissolved in DCE (20 mL). Phosphorus oxychloride (0.91 mL, 9.94 mmol) was added, and the mixture was warmed to reflux, reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 19B (250 mg, yield: 64%).

[0314] LCMS m / z = 228.1 [M+H] +< Step 3: Preparation of 19C

[0315] Compound 19B (250 mg, 1.10 mmol) was dissolved in DCM (10 mL). NBS (215.36 mg, 1.21 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-50 / 100) to obtain compound 19C (280 mg, yield: 83%).

[0316] LCMS m / z = 305.90 [M+H] +< Step 4: Preparation of 19D

[0317] Compound 19C (280 mg, 0.91 mmol) and zinc cyanide (220 mg, 2.06 mmol) were added to a 50 mL single-necked flask, and then zinc powder (150 mg, 2.29 mmol), 1,1'-bis(diphenylphosphino)ferrocene (302.69 mg, 0.55 mmol), tris(dibenzylidene-BASE acetone)dipalladium (250 mg, 0.27 mmol) and N,N-dimethylacetamide (10 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 50 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain compound 19D (210 mg, yield: 91%).

[0318] LCMS m / z = 253.10 [M+H] +< Step 5: Preparation of 19E

[0319] In an ice bath, ammonium chloride (221.98 mg, 4.15 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (2.07 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 19D (210 mg, 0.83 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 19E (200 mg, yield: 89%).

[0320] LCMS m / z = 270.2 [M+H] +< Step 6: Preparation of 19F

[0321] Compound 19E (100 mg, 0.37 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (201.70 mg, 0.55 mmol) and potassium bicarbonate (111.13 mg, 1.11 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 19F (190 mg, yield: 87%).

[0322] LCMS m / z = 587.2 [M+H] +< Step 7: Preparation of compound 19

[0323] Compound 19F (190 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain the trifluoroacetate of compound 19 (160 mg).

[0324] LCMS m / z = 573.1 [M+H] +<

[0325] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.41 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.36 - 7.10 (m, 5H), 7.04 (dd, 1H), 6.98-6.79 (m, 2H), 4.51 (s, 2H), 2.93 (s, 2H), 1.79 (s, 3H), 1.10 (s, 6H).Preparation of compound 19-1 and compound 19-2:

[0326] Compound 19 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: Waters 150 Prep-SFC; chromatographic column: AD; column temperature: 35°C; mobile phase A: CO 2 , and mobile phase B: methanol / acetonitrile (aqueous ammonia 0.1%); gradient: B: 55%; back pressure: 100 bar; cycle: 5.3 min; detection wavelength: 220 nm; flow rate: 100 ml / min.

[0327] Analysis conditions: instrument: SHIMADZU LC-30AD sf; chromatographic column: AD; mobile phase A: CO 2 , and mobile phase B: methanol and acetonitrile (0.05% DEA); flow rate: 3 ml / min; column temperature: 35°C; detection wavelength: 220 nm.

[0328] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 19-1 (56 mg) and compound 19-2 (61 mg). Compound 19-1: retention time under analysis conditions: 0.519 min, LCMS m / z = 573.2 [M+H] +<

[0329] 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.96 - 9.69 (m, 1H), 9.00 (dd, 1H), 8.43 (dd, 1H), 7.38 - 7.06 (m, 5H), 6.98 (dd, 1H), 6.89 - 6.70 (m, 2H), 4.49 (s, 2H), 2.93 (s, 2H), 1.78 (s, 3H), 1.09 (s, 6H).Compound 19-2: retention time under analysis conditions: 1.553 min, LCMS m / z = 573.1 [M+H] +<

[0330] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.85 - 11.05 (m, 1H), 9.00 (dd, 1H), 8.43 (dd, 1H), 7.37 - 7.09 (m, 5H), 6.98 (dd, 1H), 6.87 - 6.71 (m, 2H), 4.49 (s, 2H), 2.93 (s, 2H), 1.78 (s, 3H), 1.09 (s, 6H).Example 20:

[0331]

[0332] With reference to the synthesis for Example 6 and Example 21, compound 20 (0.035 g) was obtained.

[0333] LCMS m / z = 645.1 [M+H] +<

[0334] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.55 (s, 1H), 8.66-8.61 (m, 2H), 7.26 (s, 1H), 6.90 (br.s, 2H), 4.86 (t, 2H), 3.04 - 2.86 (m, 4H), 1.81 (s, 3H), 1.10 (s, 6H).Example 21:

[0335] Step 1: Preparation of 21A

[0336] Ethyl 2-cyanopropionate (5.00 g, 39.32 mmol) was added to a 100 mL reaction flask. In an ice bath, trimethylchlorosilane (8.54 g, 78.64 mmol) was added dropwise, and then water (1.42 g, 78.64 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 4 h. 50 mL of water was added to the reaction solution. The mixture was extracted with n-hexane, and the aqueous phase was separated, collected, basified with a saturated aqueous sodium bicarbonate solution, and extracted 3 times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain compound 21A (1.46 g, yield: 25%).

[0337] LCMS m / z = 146.1 [M+H] +< Step 2: Preparation of 21B

[0338] Compound 2D (0.50 g, 2.11 mmol) and 21A (0.31 g, 2.15 mmol) were dissolved in ethyl acetate (10 mL), and then silver trifluoromethanesulphonate (0.54 g, 2.11 mmol) was added. After the addition, the mixture was warmed to 90°C and stirred for 2 h in the dark. The reaction solution was cooled to room temperature and subjected to suction filtration to remove solids. The filter cake was washed 3 times with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21B (0.30 g, yield: 31%).

[0339] LCMS m / z = 284.40 [M+H] +< Step 3: Preparation of21C

[0340] Compound 21B (0.30 g, 1.06 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen atmosphere, lithium bis(trimethylsilyl)amide (0.59 mL, 1.17 mmol, 2 M) was added dropwise in an ice bath, and the mixture was reacted at the same temperature for 0.5 hours. Then, N-bromosuccinimide (0.21 g, 1.17 mmol) was added. After the addition, the mixture was reacted for 0.5 hours in an ice bath. The reaction was quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21C (0.217 g, yield: 56%).

[0341] LCMS m / z = 362.40 [M+H] +< Step 4: Preparation of 21D

[0342] Compound 21C (0.217 g, 0.60 mmol) and malononitrile (0.079 g, 1.20 mmol) were dissolved in tetrahydrofuran (10 mL). In an ice bath, DBU (0.18 g, 1.20 mmol) was added dropwise. After the addition, the mixture was reacted in an ice bath for 0.5 hours. The reaction was quenched with saturated ammonium chloride and extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 21D (0.16 g, yield: 76%).

[0343] LCMS m / z = 348.1 [M+H] +< Step 5: Preparation of21E

[0344] Compound 6F (0.10 g, 0.29 mmol), 21D (0.10 g, 0.29 mmol) and potassium bicarbonate (0.087 g, 0.87 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred and reacted for 16 hours, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 21E (0.142 g, yield: 76%).

[0345] LCMS m / z = 643.2[M+H] +< Step 6: Preparation of compound 21

[0346] Compound 21E (0.142 g, 0.22 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.092 g, 2.2 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid, with white solids precipitated. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 21 (0.095 g, yield: 67%).

[0347] LCMS m / z = 629.1 [M+H] +<

[0348] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.50-11.80 (m, 1H), 11.47 (s, 1H), 8.65-8.61 (m, 2H), 7.75 (s, 1H), 6.79 - 6.41 (m, 2H), 4.86 (t, 2H), 3.08-2.87 (m, 2H), 2.73-2.61 (m, 2H), 1.82 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 22:

[0349]

[0350] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 22 (0.031 g) was obtained.

[0351] LCMS m / z = 611.2 [M+H] +<

[0352] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 8.76 (d, 1H), 8.52 (d, 1H), 7.67-7.59 (m, 1H), 7.27 (s, 1H), 7.13-6.90 (m, 2H), 4.92 (t, 2H), 3.05 - 2.89 (m, 4H), 1.83 (s, 3H), 1.11 (s, 6H).Example 23:

[0353]

[0354] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 23 (0.021 g) was obtained.

[0355] LCMS m / z = 573.2 [M+H] +<

[0356] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.71 (d, 1H), 8.40 (d, 1H), 7.62-7.51 (m, 1H), 7.44-7.32 (m, 1H), 7.30 - 7.12 (m, 4H), 7.05-6.80 (m, 2H), 5.86 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 24:

[0357]

[0358] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 24 (0.117 g) was obtained.

[0359] LCMS m / z = 591.2 [M+H] +<

[0360] 1< H NMR (400 MHz, DMSO-d 6 ) δ 13.00-11.60 (m, 1H), 11.53 (s, 1H), 8.70 (d, 1H), 8.39 (d, 1H), 7.63-7.51 (m, 1H), 7.46-7.35 (m, 1H), 7.26 (s, 1H), 7.23-7.13 (m, 1H), 7.08-6.98 (m, 1H), 6.98-6.82 (m, 2H), 5.91 (s, 2H), 2.94 (s, 2H), 1.82 (s, 3H), 1.10 (s, 6H).Example 25:

[0361]

[0362] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 25 (250 mg) was obtained.

[0363] LCMS m / z = 645.1 [M+H] +<

[0364] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.35-11.95 (m, 1H), 11.43 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 7.28 (s, 1H), 6.89 (br.s, 2H), 4.98 (t, 2H), 3.09 - 2.88 (m, 4H), 1.83 (s, 3H), 1.10 (s, 6H).Example 26:

[0365]

[0366] With reference to the synthesis for Example 6, Example 20 and Example 21, compound 26 (100 mg) was obtained.

[0367] LCMS m / z = 629.1 [M+H] +<

[0368] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.16 (br.s, 1H), 11.37 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 6.73 - 6.45 (m, 2H), 4.98 (t, 2H), 3.08 - 2.91 (m, 2H), 2.75-2.61 (m, 2H), 1.84 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).Example 27:

[0369]

[0370] With reference to the synthesis for Example 16, the trifluoroacetate of compound 27 (10 mg) was obtained.

[0371] LCMS m / z = 578.3[M+H] +< Example 28:

[0372]

[0373] With reference to the synthesis for Example 15, the trifluoroacetate of compound 28 (20 mg) was obtained.

[0374] LCMS m / z = 623.5[M-H] -<

[0375] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 8.37 (dd, 1H), 8.15 - 8.05 (m, 1H), 7.44 - 7.30 (m, 1H), 7.25 (s, 1H), 7.21 - 7.00 (m, 4H), 5.18 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 29:

[0376]

[0377] With reference to the synthesis for Example 5, compound 29 (6 mg) was obtained.

[0378] LCMS m / z = 611.1[M+H] +<

[0379] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.87 - 11.06 (m, 1H), 9.17 (d, 1H), 8.67 (d, 1H), 7.56 (dd, 1H), 7.32 - 7.07 (m, 3H), 3.41 - 3.33 (m, 2H), 2.99 - 2.81 (m, 4H), 1.81 (s, 3H), 1.10 (s, 6H).Example 30:

[0380]

[0381] With reference to the synthesis for Example 6, Example 20 and Example 21, the trifluoroacetate of compound 30 (170 mg) was obtained.

[0382] LCMS m / z = 629.1 [M+H] +<

[0383] 1< H NMR (400 MHz, DMSO-d 6 )δ 11.47 (s, 1H), 9.23 (s, 1H), 8.31 (s, 1H), 7.26 (s, 1H), 6.88 (s, 2H), 5.00 (t, 2H), 3.10 - 2.86 (m, 4H), 1.82 (s, 3H), 1.10 (s, 6H).Example 31:

[0384] Step 1: Preparation of31A

[0385] Compound 11C (0.14 g, 0.47 mmol), 2F (0.30 g) and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 31A (70 mg, yield: 23%).

[0386] LCMS m / z = 658.3 [M+H] +< Step 2: Preparation of compound 31

[0387] Compound 31A (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL). Lithium hydroxide (0.026 g, 1.09 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 31 (20 mg, yield: 28%).

[0388] LCMS m / z = 644.2 [M+H] +<

[0389] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 7.83 (dd, 1H), 7.35 (dd, 1H), 7.26 (s, 1H), 7.17 - 6.99 (m, 2H), 6.96 - 6.87 (m, 1H), 4.22 (t, 2H), 2.93 (s, 2H), 2.83 - 2.63 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 31-1 and compound 31-2:

[0390] Compound 31 (180 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol / isopropanol = 1 / 1 (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 25%; c. flow rate: 40 mL / min.

[0391] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 31-1 (75 mg) and compound 31-2 (80 mg). Compound 31-1: retention time under chiral preparative conditions: 4.37 min, LCMS m / z = 644.2 [M+1] +<

[0392] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 7.83 (dd, 1H), 7.35 (dd, 1H), 7.26 (s, 1H), 7.14 - 6.98 (m, 2H), 6.96 - 6.86 (m, 1H), 4.21 (t, 2H), 2.93 (s, 2H), 2.84 - 2.64 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Compound 31-2: retention time under chiral preparative conditions: 6.45 min, LCMS m / z = 644.2 [M+1] +<

[0393] 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (dd, 1H), 7.35 (dd, 1H), 7.25 (s, 1H), 7.12 - 7.00 (m, 2H), 6.95 - 6.87 (m, 1H), 4.22 (t, 2H), 2.93 (s, 2H), 2.82 - 2.63 (m, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 32:

[0394] Step 1: Preparation of 32A

[0395] Compound methyl 2-bromo-5-chlorobenzoate (5 g, 20.07 mmol) and o-fluorophenylacetic acid (3.40 g, 22.08 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (25.09 mL, 2 M, 50.17 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (150 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 32A (5.7 g, yield: 86%).

[0396] LCMS m / z = 327.0 [M+H] +< Step 2: Preparation of 32B

[0397] Compound 32A (3 g, 9.16 mmol) was dissolved in methanol (30 mL). Aminoguanidine hydrochloride (1.52 g, 13.75 mmol) and boron trifluoride diethyl etherate (2.26 mL, 18.32 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 32B, which was directly used in the next step.

[0398] LCMS m / z = 383.3 [M+H] +< Step 3: Preparation of32C

[0399] Compound 32B (600 mg, 1.56 mmol) was dissolved in DMF (10 mL). N,N-dimethylethylenediamine (206.27 mg, 2.34 mmol) and cuprous iodide (148.55 mg, 0.78 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 4 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 32C (200 mg, yield: 49%).

[0400] LCMS m / z = 261.2 [M+H] +< Step 4: Preparation of 32D

[0401] Compound 32C (60 mg, 0.23 mmol), 2F (107.15 mg) and caesium carbonate (149.88 mg, 0.46 mmol) were mixed and dissolved in DMF (3 mL). The mixture was warmed to 100°C, stirred for 40 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 115-111) to obtain compound 32D (60 mg, yield: 42%).

[0402] LCMS m / z = 620.2[M+H] +< Step 5: Preparation of compound 32

[0403] Compound 32D (60 mg, 0.097 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (40.70 mg, 0.97 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous hydrochloric acid solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 32 (15 mg).

[0404] LCMS m / z = 606.2[M+H] +<

[0405] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.85 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 7.39 (t, 1H), 7.35 - 7.02 (m, 6H), 4.40 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 32-1 and compound 32-2:

[0406] Compound 32 (65 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: isopropanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0407] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 32-1 (20 mg) and compound 32-2 (25 mg).Compound 32-1: retention time under chiral preparative conditions: 7.40 min, LCMS m / z = 606.0 [M+1] +< Compound 32-2: retention time under chiral preparative conditions: 11.97 min, LCMS m / z = 606.0 [M+1] +< Example 33:

[0408]

[0409] With reference to the synthesis for Example 17, the trifluoroacetate of compound 33 (15 mg) was obtained.

[0410] LCMS m / z = 612.3 [M+H] +<

[0411] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.86 (dd, 1H), 7.81 (dd, 1H), 7.75 (s, 1H), 7.47 - 7.37 (m, 1H), 7.20 - 6.46 (m, 2H), 3.35 - 3.23 (m, 2H), 2.87 - 2.72 (m, 2H), 2.71 - 2.61 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 34:

[0412]

[0413] With reference to the synthesis for Example 4, the trifluoroacetate of compound 34 (8 mg) was obtained.

[0414] LCMS m / z = 590.2 [M+H] +<

[0415] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 8.84 (d, 1H), 7.82 (d, 1H), 7.74 (s, 1H), 7.52 (dd, 1H), 7.42 - 7.27 (m, 2H), 7.24 - 7.13 (m, 2H), 7.03 - 6.65 (m, 2H), 4.40 (s, 2H), 2.71 - 2.58 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H).Example 35:

[0416] Step 1: Preparation of 35B

[0417] Compound 35A (CAS: 1361570-31-1, synthesised with reference to US 2013210824) (1 g, 3.23 mmol) was dissolved in DMSO (5 mL). Sodium chloride (0.29 g, 4.93 mmol) and water (0.5 mL) were added sequentially. The mixture was warmed to 160°C, stirred for 30 min, cooled to room temperature and extracted with 10 mL of water and 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 35B (0.7 g, yield: 86%).Step 2: Preparation of35C

[0418] Compound 35B (0.7 g, 2.79 mmol) was dissolved in ethylene glycol (7 mL). Hydrazine hydrate (1.24 g, 19.75 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 14 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 35C (0.35 g, yield: 51%).

[0419] LCMS m / z = 246.1 [M+H] +< Step 3: Preparation of35D

[0420] Compound 35C (0.1 g, 0.41 mmol), 2F (0.21 g) and potassium carbonate (0.057 g, 0.41 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 35D (0.22 g, yield: 88%).

[0421] LCMS m / z = 605.1 [M+H] +< Step 4: Preparation of compound 35

[0422] Compound 35D (0.22 g, 0.36 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.086 g, 3.59 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 35 (0.15 g, yield: 70%).

[0423] LCMS m / z = 591.2 [M+H] +<

[0424] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.55 (s, 1H), 9.04 (dd, 1H), 8.68 (d, 1H), 7.42 - 7.35 (m, 1H), 7.33 - 7.05 (m, 6H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 35-1 and compound 35-2:

[0425] Compound 35 (140 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 54 ml / min.

[0426] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0427] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 35-1 (60 mg) and compound 35-2 (70 mg).Compound 35-1: retention time under analysis conditions: 3.4 min, LCMS m / z = 591.1 [M+H] +< Compound 35-2: retention time under analysis conditions: 5.2 min, LCMS m / z = 591.1[M+H] +< Example 36:

[0428] Step 1: Preparation of36A

[0429] Compound 2,3-difluorophenylacetic acid (1 g, 5.81 mmol) was dissolved in methanol (10 mL), and p-toluenesulphonic acid monohydrate (0.11 g, 0.58 mmol) was added. The mixture was warmed to reflux and reacted for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (10 mL×2) and a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure, and the residue was directly used in the next step.Step 2: Preparation of36B

[0430] Compound 36A (1.11 g, 5.95 mmol) was dissolved in THF (10 mL). LiHMDS (7.14 mmol, 7.14 mL, 1 N) was slowly added dropwise in a dry ice-ethanol bath. After the addition, the mixture was stirred at -70°C for 1 h. At this temperature, a solution of 3,5-difluoropicolinoyl chloride (CAS: 1048340-35-7, synthesised with reference to WO 2011158149) (1.27 g, 7.14 mmol) in THF (10 mL) was slowly added dropwise. After the addition, the mixture was naturally warmed to room temperature, and the reaction was quenched with 10 mL of a saturated aqueous ammonium chloride solution and extracted with 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36B (0.5 g, yield: 26%).Step 3: Preparation of36C

[0431] Compound 36B (0.5 g, 1.53 mmol) was dissolved in DMSO (5 mL). Sodium chloride (0.13 g, 2.29 mmol) and water (0.5 mL) were added sequentially. The mixture was warmed to 160°C, stirred for 30 min, cooled to room temperature and extracted with 10 mL of water and 20 mL of ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL×1), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36C (0.3 g, yield: 73%).Step 4: Preparation of 36D

[0432] Compound 36C was dissolved in ethylene glycol (4 mL). Hydrazine hydrate (0.49 g, 7.86 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 8 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 36D (0.14 g, yield: 48%).

[0433] LCMS m / z = 264.3 [M+H] +< Step 5: Preparation of36E

[0434] Compound 36D (0.1 g, 0.38 mmol), 2F (0.19 g) and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 36E (0.2 g, yield: 84%).

[0435] LCMS m / z = 623.2 [M+H] +< Step 6: Preparation of compound 36

[0436] Compound 36E (0.2 g, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.077 g, 3.2 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 36 (0.12 g, yield: 61%).

[0437] LCMS m / z = 609.2 [M+H] +<

[0438] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.54 (s, 1H), 9.05 (dd, 1H), 8.69 (d, 1H), 7.42 - 7.02 (m, 6H), 4.49 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.11 (s, 6H).Preparation of compound 36-1 and compound 36-2:

[0439] Compound 36 (100 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 30%; flow rate: 54 ml / min.

[0440] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0441] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 36-1 (39 mg) and compound 36-2 (35 mg).Compound 36-1: retention time under analysis conditions: 3.3 min, LCMS m / z = 609.2 [M+H] +< Compound 36-2: retention time under analysis conditions: 5.4 min, LCMS m / z = 609.2 [M+H] +< Example 37:

[0442] Step 1: Preparation of37A

[0443] THF (10 mL) was placed in a three-necked flask. High-purity zinc powder (0.74 g, 11.31 mmol) was added. The mixture was purged three times with nitrogen, and 1,2-dibromoethane (0.11 g, 0.56 mmol) was added. After the addition, the mixture was warmed to 70°C, stirred for 10 min and cooled to room temperature. Trimethylchlorosilane (0.061 g, 0.56 mmol) was slowly added. After the addition, the mixture was stirred vigorously at room temperature for 10 min. A solution of 1,1,1,2,2-pentafluoro-4-iodobutane (1.55 g, 5.66 mmol) in THF (5 mL) was slowly added dropwise. After the addition, the mixture was further stirred at room temperature for 2 h, and the resulting reagent was set aside for subsequent use. In another reaction flask, 3,5-difluoropicolinoyl chloride (CAS: 1048340-35-7, synthesised with reference to WO 2011158149) (0.5 g, 2.82 mmol) was dissolved in THF (10 mL). Bis(triphenylphosphine)palladium dichloride (0.20 g, 0.28 mmol) was added, and the mixture was purged three times with nitrogen. At room temperature, the above-mentioned reagent was slowly added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 2 h. The reaction was quenched with 20 mL of saturated ammonium chloride and extracted with 20 mL of ethyl acetate and 10 mL of water. The organic phase was washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 37A (0.22 g, yield: 27%).

[0444] LCMS m / z = 290.1 [M+H] +< Step 2: Preparation of37B

[0445] Compound 37A (0.22 g, 0.76 mmol) was dissolved in ethylene glycol (3 mL). Hydrazine hydrate (0.38 g, 7.59 mmol, wt% = 80%) was added. The mixture was warmed to 100°C and stirred for 30 min, then warmed to 120°C and stirred for 2 h, and cooled to room temperature. With stirring, 6 mL of water was slowly added dropwise, with the solids precipitated. The resulting mixture was filtered. The filter cake was dried under reduced pressure to obtain compound 37B (0.1 g, yield: 46%).

[0446] LCMS m / z = 284.2 [M+H] +< Step 3: Preparation of37C

[0447] Compound 37B (0.1 g, 0.35 mmol), 2F (0.18 g) and potassium carbonate (0.097 g, 0.70 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 80°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 37C (0.15 g, yield: 66%).

[0448] LCMS m / z = 643.1 [M+H] +< Step 4: Preparation of compound 37

[0449] Compound 37C (0.15 g, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.056 g, 2.33 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 37 (90 mg, yield: 62%).

[0450] LCMS m / z = 629.2 [M+H] +<

[0451] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s, 1H), 11.55 (s, 1H), 9.06 (dd, 1H), 8.72 (dd, 1H), 7.56 - 6.90 (m, 3H), 3.40-3.32 (m, 2H), 2.97 - 2.81 (m, 4H), 1.82 (s, 3H), 1.11 (s, 6H).Preparation of compound 37-1 and compound 37-2:

[0452] Compound 37 (80 mg) was subjected to chiral separation and purification. Preparative conditions: instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm). The sample was dissolved in DMF and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); isocratic elution, mobile phase B: 15%; flow rate: 42 ml / min.

[0453] Analysis conditions: instrument: UPC2; chromatographic column: IG (3 mm×50 mm). The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. Preparative chromatography conditions: mobile phase A: CO 2 , and mobile phase B: methanol (containing 0.5% aqueous ammonia); gradient elution, mobile phase B: 10%-40%, time: 5 min; isocratic elution, mobile phase B: 40%; flow rate: 1.5 ml / min.

[0454] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 37-1 (38 mg) and compound 37-2 (35 mg).Compound 37-1: retention time under analysis conditions: 1.9 min, LCMS m / z = 629.2 [M+H] +< Compound 37-2: retention time under analysis conditions: 2.7 min, LCMS m / z = 629.2 [M+H] +< Example 38:

[0455] Step 1: Preparation of 38A

[0456] Compound 2,4-difluoronitrobenzene (1 g, 6.29 mmol) and 2-fluorobenzylamine (0.86 g, 6.88 mmol) were dissolved in DMSO (5 mL). Diisopropylethylamine (1.22 g, 9.44 mmol) was added, and the mixture was stirred at room temperature for 4 h and extracted with 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL×3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 5) to obtain compound 38A (1.1 g, yield: 66%).Step 2: Preparation of 38B

[0457] Compound 38A (1.1 g, 4.16 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (2.22 g, 41.49 mmol) and iron powder (2.32 g, 41.56 mmol) were added sequentially. After the addition, the mixture was warmed to 75°C, stirred for 1.5 h, cooled to room temperature and filtered. The filter cake was washed with 20 mL of dichloromethane. The filtrates were combined and washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 4) to obtain compound 38B (0.8 g, yield: 82%).Step 3: Preparation of38C

[0458] Compound 38B (0.8 g, 3.42 mmol) was dissolved in THF (10 mL). N,N'-carbonyldiimidazole (0.83 g, 5.13 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 h. 20 mL of dichloromethane was added. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was slurried with 20 mL of methyl tert-butyl ether / petroleum ether (V / V = 1 / 1) to obtain compound 38C (0.45 g, yield: 50%).

[0459] LCMS m / z = 261.1 [M+H] +< Step 4: Preparation of 38D

[0460] Compound 38C (0.10 g, 0.40 mmol), 2F (0.20 g) and potassium carbonate (0.11 g, 0.80 mmol) were mixed and dissolved in DMF (5 mL). The mixture was warmed to 100°C, stirred for 16 h, cooled to room temperature and extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with a saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 1) to obtain compound 38D (70 mg, yield: 28%).

[0461] LCMS m / z = 620.3 [M+H] +< Step 5: Preparation of compound 38

[0462] Compound 38D (0.07 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL). Lithium hydroxide (0.026 g, 1.1 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-50 / 50) to obtain the trifluoroacetate of compound 38 (30 mg).

[0463] LCMS m / z = 606.0 [M+H] +<

[0464] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 7.84 (dd, 1H), 7.41 - 7.32 (m, 1H), 7.31 - 6.98 (m, 7H), 6.94 - 6.87 (m, 1H), 5.15 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.15 - 1.01 (m, 6H).Preparation of compound 38-1 and compound 38-2:

[0465]

[0466] Compound 38 (300 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm). 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. the mobile phase consists of systems A and B: mobile phase A: CO 2 ; mobile phase B: methanol (aqueous ammonia 0.05%); b. isocratic elution, mobile phase B: 40%; c. flow rate: 40 mL / min.

[0467] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 38-1 (110 mg) and compound 38-2 (120 mg).Compound 38-1: retention time under chiral preparative conditions: 7.78 min, LCMS m / z = 606.0 [M+1] +< Compound 38-2: retention time under chiral preparative conditions: 12.85 min, LCMS m / z = 606.2 [M+1] +< Example 39:

[0468]

[0469] With reference to the synthesis for Example 38, the trifluoroacetate of compound 39 (25 mg) was obtained.

[0470] LCMS m / z = 578.2 [M+H] +< Example 40:

[0471] Step 1: Preparation of 40B

[0472] Compound methyl 2-bromo-6-fluorobenzoate (2 g, 8.58 mmol) and 2-fluorophenylacetic acid (1.45 g, 90.48 mmol) were dissolved in THF (40 mL). At - 78°C, sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (60 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 40B (1.8 g, yield: 67%).Step 2: Preparation of 40C

[0473] Compound 40B (1.6 g, 5.14 mmol) was dissolved in methanol (10 mL). Aminoguanidine hydrochloride (0.57 g, 7.71 mmol) and boron trifluoride diethyl etherate (1.1 mL, 8.91 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain compound 40C, which was directly used in the next step.

[0474] LCMS m / z = 367.0[M+H] +< Step 3: Preparation of 40D

[0475] Compound 40C (0.1 g, 0.27 mmol), 21D (0.094 g, 0.27 mmol) and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (15 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 40D (90 mg, yield: 50%).Step 4: Preparation of 40E

[0476] Compound 40D (90 mg, 0.13 mmol) was dissolved in DMF (3 mL). N,N-dimethylethylenediamine (17 mg, 0.19 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 40E (30 mg, yield: 39%).Step 5: Preparation of compound 40

[0477] Compound 40E (0.03 g, 0.051 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.012 g, 0.51 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 40 (10 mg, yield: 34%).

[0478] LCMS m / z = 572.5[M-H] -<

[0479] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 8.67 (d, 1H), 7.75 (s, 1H), 7.56 - 7.46 (m, 1H), 7.33 - 7.25 (m, 1H), 7.24 - 7.16 (m, 2H), 7.14 - 7.00 (m, 2H), 6.96 - 6.74 (m, 2H), 4.43 (s, 2H), 2.71 - 2.61 (m, 2H), 1.81 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H).Example 41:

[0480] Step 1: Preparation of 41B

[0481] Compound 40C (0.1 g, 0.27 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (98 mg, 0.27 mmol) and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (5 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 41B (90 mg, yield: 49%).Step 2: Preparation of 41C

[0482] Compound 41B (90 mg, 0.90 mmol) was dissolved in DMF (3 mL). N,N-dimethylethylenediamine (11 mg, 0.13 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 41C (28 mg, yield: 36%).Step 5: Preparation of compound 41

[0483] Compound 41C (0.028 g, 0.046 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.011 g, 0.46 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 41 (10 mg, yield: 37%).

[0484] LCMS m / z = 588.5[M-H] -<

[0485] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 8.68 (d, 1H), 7.56 - 7.48 (m, 1H), 7.33 - 7.02 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Preparation of compound 41-1 and compound 41-2:

[0486]

[0487] Compound 41 (90 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO 2 ; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 45%; c. flow rate: 44 ml / min.

[0488] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 41-1 (40 mg) and compound 41-2 (40 mg).Compound 41-1: retention time under chiral preparative conditions: 4.53 min, LCMS m / z = 590.5 [M+H] +<

[0489] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 8.68 (d, 1H), 7.57 - 7.43 (m, 1H), 7.35 - 6.98 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Compound 41-2: retention time under chiral preparative conditions: 23.08 min, LCMS m / z = 590.5 [M+H] +<

[0490] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 8.68 (d, 1H), 7.59 - 7.43 (m, 1H), 7.36 - 6.93 (m, 8H), 4.43 (s, 2H), 2.93 (s, 2H), 1.81 (s, 3H), 1.10 (s, 6H).Example 42:

[0491]

[0492] With reference to the synthesis for Example 40, compound 42 (10 mg) was obtained.

[0493] LCMS m / z = 592.2[M+H] +<

[0494] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.50 (s, 1H), 8.67 (d, 1H), 7.75 (s, 1H), 7.57 - 7.48 (m, 1H), 7.37 - 7.25 (m, 1H), 7.16 - 6.99 (m, 3H), 6.99 - 6.68 (m, 2H), 4.48 (s, 2H), 2.71 - 2.61 (m, 2H), 1.82 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H).Example 43:

[0495] Step 1: Preparation of 43B

[0496] Compound 40A (2 g, 8.58 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (3.3 g, 17 mmol) were dissolved in THF (100 mL). At -78°C, sodium bis(trimethylsilyl)amide (18 mL, 2 M, 36 mmol) was added, and the mixture was stirred and reacted at this temperature for 15 min, and then warmed to 0°C and reacted for 2 h. The reaction was quenched with 1 N hydrochloric acid (160 mL), and the mixture was stirred overnight at room temperature and extracted with ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium bicarbonate solution, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 20) to obtain compound 43B (0.6 g, yield: 20%).Step 2: Preparation of 43C

[0497] Compound 43B (0.6 g, 1.72 mmol) was dissolved in methanol (20 mL). Aminoguanidine hydrochloride (0.38 g, 3.44 mmol) and boron trifluoride diethyl etherate (0.49 g, 3.44 mmol) were added. The tube was sealed, warmed to 100°C, reacted for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43C (0.3 g, yield: 43%).Step 3: Preparation of 43D

[0498] Compound 43C (0.34 g, 0.83 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (300 mg, 0.83 mmol) and potassium bicarbonate (83 mg, 0.83 mmol) were mixed and dissolved in tert-butanol (5 mL). The tube was sealed, warmed to 130°C, stirred for 3 h and cooled to room temperature. A 1 N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was stirred for layer separation. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43D (200 mg, yield: 34%).

[0499] LCMS m / z = 722.1[M+H] +< Step 4: Preparation of 43E

[0500] Compound 43D (200 mg, 0.28 mmol) was dissolved in DMF (5 mL). N,N-dimethylethylenediamine (37 mg, 0.42 mmol) and cuprous iodide (53 mg, 0.28 mmol) were added, and the mixture was purged three times with nitrogen. Under nitrogen atmosphere, the mixture was reacted for 2 h. Ethyl acetate and water were added, and the mixture was stirred for layer separation. The organic layer was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-10 / 1) to obtain compound 43E (120 mg, yield: 68%).

[0501] LCMS m / z = 642.2[M+H] +< Step 5: Preparation of compound 43

[0502] Compound 43E (0.12 g, 0.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide (0.011 g, 0.46 mmol) was added. The mixture was warmed to 60°C, stirred for 1 h and cooled to room temperature. The reaction solution was adjusted to pH = 3-4 by adding a 1 N aqueous HCl solution. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate of compound 43 (40 mg).

[0503] LCMS m / z = 628.2[M+H] +<

[0504] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.68 (d, 1H), 7.61 - 7.46 (m, 1H), 7.25 (s, 1H), 7.22 - 6.96 (m, 3H), 3.42 - 3.28 (m, 2H), 2.93 (s, 2H), 2.85 - 2.69 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).

[0505] The racemate of compound 43 (130 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 22%; c. flow rate: 43 ml / min.

[0506] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 43-1 (60 mg) and compound 43-2 (60 mg). Compound 43-1: retention time under chiral preparative conditions: 4.05 min, LCMS m / z = 628.2 [M+H] +<

[0507] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.53 (s, 1H), 8.68 (d, 1H), 7.58 - 7.49 (m, 1H), 7.25 (s, 1H), 7.22 - 6.98 (m, 3H), 3.39 - 3.32 (m, 2H), 2.94 (s, 2H), 2.88 - 2.64 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Compound 43-2: retention time under chiral preparative conditions: 9.87 min, LCMS m / z = 628.2 [M+H] +<

[0508] 1< H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.68 (d, 1H), 7.58 - 7.48 (m, 1H), 7.25 (s, 1H), 7.22 - 6.95 (m, 3H), 3.40 - 3.32 (m, 2H), 2.94 (s, 2H), 2.86 - 2.67 (m, 2H), 1.82 (s, 3H), 1.11 (s, 6H).Example 44:

[0509]

[0510] With reference to the synthesis for Example 35, compound 44 (50 mg) was obtained.

[0511] LCMS m / z = 579.3 [M+H] +< Example 45:

[0512] Step 1: Preparation of 45A

[0513] To a reaction flask were added 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-carboxamide (CAS: 1407815-26-2, 0.2 g, 0.62 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2,0.23 g, 0.62 mmol), sodium bicarbonate (0.21 g, 2.48 mmol) and tert-butanol (10 mL). The mixture was heated and reacted overnight in an oil bath at 85°. To the reaction solution was added an appropriate amount of silica gel, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 45A (0.23 g, yield: 58%).Step 2: Preparation of compound 45

[0514] To a reaction flask were added 45A (0.23 g, 0.36 mmol), lithium hydroxide monohydrate (0.15 g, 3.60 mmol), 1,4-dioxane (5 mL) and water (3 mL). The mixture was stirred overnight at room temperature reaction. Ethyl acetate and water were added, and the mixture was adjusted to pH 2-3 with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain compound 45 (0.19 g, yield: 84%).

[0515] LCMS m / z = 628.0[M+H] +<

[0516] Compound 45 (180 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm × 250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 25%; c. flow rate: 40 ml / min.

[0517] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 45-1 (72 mg) and compound 45-2 (70 mg). Compound 45-1: retention time under chiral preparative conditions: 8.1 min, LCMS m / z = 628.3[M+H] +<

[0518] 1< H NMR (400 MHz, CDCl 3 / CD 3 OD(v / v) = 1 / 1) δ 8.68 (dd, 1H), 8.16 - 8.05 (m, 1H), 7.14 - 6.91 (m, 2H), 3.33 - 3.28 (m, 2H), 3.13 - 2.98 (m, 2H), 2.94 - 2.76 (m, 2H), 1.88 (s, 3H), 1.24 (s, 3H), 1.21 (s, 3H).Compound 45-2: retention time under chiral preparative conditions: 27.1 min, LCMS m / z = 628.3[M+H] +<

[0519] 1< H NMR (400 MHz, CDCl 3 / CD 3 OD(v / v) = 1 / 1) δ 8.68 (dd, 1H), 8.09 - 7.93 (m, 1H), 7.12 - 6.90 (m, 2H), 3.34 - 3.25 (m, 2H), 3.14 - 2.98 (m, 2H), 2.94 - 2.74 (m, 2H), 1.88 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H).Example 46:

[0520] Step 1: Preparation of 46A

[0521] To a reaction flask were added 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-carboxamide (CAS: 1407815-26-2, 0.16 g, 0.49 mmol), 21D (0.17 g, 0.49 mmol), sodium bicarbonate (0.16 g, 1.96 mmol) and tert-butanol (10 mL). The mixture was heated and reacted overnight in an oil bath at 85°C. To the reaction solution was added an appropriate amount of silica gel, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 46A (0.23 g, yield: 75%).Step 2: Preparation of compound 46

[0522] To a reaction flask were added 46A (0.21 g, 0.34 mmol), lithium hydroxide monohydrate (0.14 g, 3.40 mmol), 1,4-dioxane (5 mL) and water (3 mL). The mixture was stirred overnight at room temperature reaction. Ethyl acetate and water were added, and the mixture was adjusted to pH 2-3 with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: DCM-CH 3 OH = 100-0 to 90-10) to obtain compound 46 (0.18 g, yield: 88%).

[0523] LCMS m / z = 612.2[M+H] +< Example 47:

[0524] Step 1: Preparation of 47A

[0525] Compound 2-(aminomethyl)-5-chloropyridine hydrochloride (1.00 g, 5.59 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.61 g, 8.38 mmol) were dissolved in DMF (20 mL). HATU (4.25 g, 11.18 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (3.61 g, 27.95 mmol) was added, and the mixture was reacted at room temperature for 1 h and extracted with water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 100 / 0-100 / 30) to obtain compound 47A (1.7 g, yield: 96%).Step 2: Preparation of 47B

[0526] Compound 47A (1.7 g, 5.37 mmol) was dissolved in phosphorus oxychloride (20 mL), and the mixture was warmed to reflux and reacted overnight, cooled to room temperature and concentrated under reduced pressure. The residue was carefully and slowly added to water, and the mixture was stirred for 5 min. Ethyl acetate was added, and the mixture was stirred for layer separation. The aqueous layer was treated with a saturated aqueous sodium bicarbonate solution and then extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-20 / 100) to obtain compound 47B (1.6 g).

[0527] LCMS m / z = 299.1 [M+H] +< Step 3: Preparation of 47C

[0528] Compound 47B (1.7 g, 5.69 mmol) was dissolved in DCM (20 mL). NBS (1.14 g, 6.26 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water was added, and the mixture was stirred for layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100-10 / 100) to obtain compound 47C (2.1 g).Step 4: Preparation of 47D

[0529] Compound 47C (2 g, 5.30 mmol) and zinc cyanide (1.24 g, 10.6 mmol) were added to a 50 mL single-necked flask, and then zinc powder (693.35 mg, 10.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.76 g, 3.18 mmol), tris(dibenzylidene-BASE acetone)dipalladium (1.46 g, 1.59 mmol) and N,N-dimethylacetamide (30 mL) were added. Under nitrogen atmosphere, the mixture was warmed to 120°C and stirred for 2 h. The reaction solution was diluted in 100 mL of ethyl acetate, washed 3 times with water and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain compound 47D (400 mg, yield: 23%).

[0530] LCMS m / z = 324.0 [M+H] +< Step 5: Preparation of 47E

[0531] In an ice bath, ammonium chloride (190 mg, 3.55 mmol) was added to a 50 mL single-necked flask. Toluene (10 mL) was added, and then trimethylaluminium (1.77 mL, 2 M in toluene) was slowly added dropwise. The mixture was warmed to room temperature, stirred and reacted for 3 h. Compound 47D (230 mg, 0.71 mmol) was dissolved in toluene and added dropwise to the reaction solution. The mixture was warmed to 110°C, stirred overnight and cooled to room temperature. In an ice bath, silica gel and 20 mL of methanol were added. The mixture was further stirred for 30 min and subjected to suction filtration. The filter cake was washed 3 times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 47E (145 mg, yield: 60%).Step 6: Preparation of 47F

[0532] Compound 47E (140 mg, 0.41 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazo-2-yl)-2-methylpropanoate (CAS: 2101649-65-2, synthesised with reference to US20170174693) (149 mg, 0.41 mmol) and sodium bicarbonate (137.78 mg, 1.64 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was warmed to 80°C, stirred overnight, cooled to room temperature, and directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 20 / 1) to obtain compound 47F (120 mg, yield: 44%).

[0533] LCMS m / z = 658.2 [M+H] +< Step 7: Preparation of compound 47

[0534] Compound 47F (120 mg, 0.18 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL). Lithium hydroxide hydrate (76 mg, 1.8 mmol) was added. The mixture was warmed to 60°C, stirred for 3 h and cooled to room temperature. In an ice bath, the mixture was acidified by adding dilute hydrochloric acid. The resulting mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95-50 / 50) to obtain compound 47 (68 mg, yield: 58%)

[0535] LCMS m / z = 644.1 [M+H] +< Compounds 47-1 and 47-2

[0536]

[0537] The racemate of compound 47 (68 mg) was subjected to chiral resolution, and the chiral resolution method was as follows: 1. instrument: SFC Prep 150 AP; chromatographic column: IG (19 mm×250 mm) 2. The sample was dissolved in methanol and filtered with a 0.45 µm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. composition of mobile phases A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia); b. isocratic elution, mobile phase B: 40%; c. flow rate: 41 ml / min.

[0538] After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compound 47-1 (30 mg) and compound 47-2 (30 mg).Compound 47-1: retention time under chiral preparative conditions: 4.85 min, LCMS m / z = 644.5 [M+H] +<

[0539] 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.30 - 11.96 (m, 1H), 11.31 (s, 1H), 8.72 - 8.62 (m, 2H), 7.23 (s, 1H), 7.12 - 7.02 (m, 1H), 6.83 - 6.67 (m, 2H), 3.39 - 3.32 (m, 2H), 2.99 - 2.78 (m, 4H), 1.78 (s, 3H), 1.11 (s, 6H).Compound 47-2: retention time under chiral preparative conditions: 19.15 min, LCMS m / z = 644.5 [M+H] +<

[0540] 1< H NMR (400 MHz, DMSO -d 6 ) δ 12.36 - 12.01 (m, 1H), 11.31 (s, 1H), 8.78 - 8.58 (m, 2H), 7.23 (s, 1H), 7.11 - 7.01 (m, 1H), 6.82 - 6.66 (m, 2H), 3.41 - 3.31 (m, 2H), 3.00 - 2.76 (m, 4H), 1.79 (s, 3H), 1.11 (s, 6H). Control compound 1 : compound 77B in WO2017112617 Biological test examples 1. cGMP detection experiment in CHO-KI / sGC cells

[0541] Stably-transfected CHO-K1 cells stably expressing sGC α1 / β1 heterodimers were constructed and named CHO-KI / sGC. The CHO-KI / sGC cells were cultured in a complete medium (FK12+10% FBS+1% penicillin-streptomycin+0.5 mg / mL hygromycin+ 0.25 mg / mL G418). On the day of the detection, the cells were reselected in EAB assay buffer (EBSS assay buffer+5 mL of MgCl2+10 mM HEPES+0.05% BSA) at a density of 2.25*10 5< / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0542] The cells were pre-incubated with 1 pM diethylenetriamine / nitric oxide (EDTA-NO) at room temperature for 30 minutes, and then different concentrations of the compounds were added. The mixture was further incubated at 37°C for 1 h. After the incubation was completed, the reaction was terminated, and intracellular cGMP levels were measured according to the instructions for the Cisbio kit (CisBio, 62GM2PEC). The maximum cGMP production relative to the positive compound was calculated according to Equation (1-1), where RLU compound represents the reading of the test compound, and RLU reference represents the maximum reading of the positive compound. Activion % = RLU compound / RUL reference * 100 %

[0543] Conclusion: The compounds of the present invention, such as the example compounds, have good stimulatory effects on cGMP production in CHO-KI / sGC cells.2. In vitro detection experiment for soluble guanylate cyclase (sGC) activity

[0544] First, 100 nL of the compounds at different concentrations were transferred to a 384-well reaction plate (Greiner, Cat. No. 784075) using Echo 655 (LABCYTE, Cat # 655), with the final DMSO concentration of 1% in the reaction mixture; 2 µL of sGC (ICE, Cat. No. S2304F-H07SH2) was added to a 384-well reaction plate, and the mixture was centrifuged at 1000 rpm for 1 min; and then 1 µL of DETA NONOate was added, and the mixture was incubated at 37°C for10 min. After the incubation was completed, 2 µL of GTP was added, and the mixture was centrifuged at 1000 rpm for 1 min and reacted at 37°C for 60 min. In the reaction system, the final concentrations of sGC, GTP, and DETA NONOate were 1.5 nM, 5 µM, and 100 µM, respectively. After the reaction was completed, 5 µL of the test mixture (PerkinElmer, Cat. No. 62GM2PEG) was added and incubated at room temperature for 60 min. The TR-FRET signal (Ratio: 665 / 620 nm) was read using a microplate reader (BMG, Cat. No. PHERAstar FSX). A nonlinear regression curve was fitted using GraphPad Prism software, and EC 50 values were calculated. Compound A (Example 1 in WO 2010065275) was used as a positive reference compound. The activation rate was calculated according to Equation 2-1, where Low control represents the TR-FRET signal value of 1 µM compound A, and High control represents the TR-FRET signal value in the DMSO well. Table 2-1 Results of enzymatic agonism and / or activation of test compounds on soluble guanylate cyclase (sGC).Compound No.EC 50 (nM)Compound No.EC 50 (nM)Compound 1-2ATrifluoroacetate of compound 23ACompound 3ACompound 24ATrifluoroacetate of compound 4ATrifluoroacetate of compound 27ATrifluoroacetate of compound 5ATrifluoroacetate of compound 28ACompound 8ACompound 29ACompound 9ACompound 31ATrifluoroacetate of compound 10ATrifluoroacetate of compound 32ACompound 11ATrifluoroacetate of compound 33ACompound 12ATrifluoroacetate of compound 34ACompound 13ACompound 35ATrifluoroacetate of compound 14ACompound 36ATrifluoroacetate of compound 15ACompound 37ACompound 16ATrifluoroacetate of compound 38ACompound 17ATrifluoroacetate of compound 39ACompound 18ACompound 40ACompound 19ACompound 41ACompound 20ACompound 42ACompound 21ACompound 44ACompound 46ACompound 45ANote: A < 20 nM, 20 nM ≤ B < 50 nM, 50 nM ≤ C < 200 nM

[0545] Conclusion: The compounds of the present invention, such as the example compounds, have good agonistic and / or activating effects on the enzyme activity of soluble guanylate cyclase (sGC).3. cGMP detection experiment in LNCap cells

[0546] LNCap is a human prostate cancer cell line that expresses sGC protein. LNCap cells were purchased from ATCC and cultured in a complete medium (RPMI-1640+10% FBS+1% PS). On the day of the detection, the cells were reselected in assay buffer (EBSS assay buffer+5 mL of MgCl2+10 mM HEPES+0.05% BSA) at a density of 2 × 10 5< / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0547] The cells were pre-incubated with 20 µM diethylenetriamine / nitric oxide (DETA-NO) at 37°C for 30 minutes, and then different concentrations of the compounds were added. The mixture was further incubated at room temperature for 1 h. After the incubation was completed, the reaction was terminated, and intracellular cGMP levels were measured according to the instructions for the CisBio kit (Cisbio, 62GM2PEC). The cGMP production relative to compound A (Example 1 in WO 2010065275) was calculated according to Equation (3-1), and EC 50 values were calculated. Sample cGMP represents the reading of the test compound, Low control GMP represents the 1% DMSO control, and High control cGMP represents the maximum cGMP reading of compound A. Table 3-1. Results of stimulatory effects of test compounds on cGMP production in LNCap cellsCompound No.EC 50 (nM)Compound 4-1<500Compound 14-1<500Compound 15-1<500Compound 17-1<500Trifluoroacetate of compound 27<500Compound 31-1<500Compound 32-1<500Compound 35-1<500Compound 41-1<500Compound 43-1<500Control compound 13220

[0548] Conclusion: The compounds of the present invention, such as the example compounds, have good stimulatory effects on cGMP production in LNCap cells.4: Pharmacokinetic test in rats (inhalation administration)

[0549] Experimental objective: In this experiment, the test compound was administered as a single dose via inhalation to SD rats, and the concentrations of the test compound in rat plasma and lungs were determined to evaluate the pharmacokinetic characteristics and bioavailability of the test compound in the rats.

[0550] Experimental animals: Male SD rats, 180-200 g, purchased from Chengdu Dossy Experimental Animals Co., Ltd.

[0551] Experimental method: On the day of the experiment, SD rats were randomly assigned into 6 groups according to body weight (for each compound), with 2 rats in each group. The rats were fasted with water available for 12 to 16 hours one day before the administration, and were fed 4 hours after the administration. Administration informationTest compoundAdministrati on dosage* (mg / kg)Administrati on concentration (mg / mL)Administrati on volume (mL / kg)Collected sampleMode of administra tionVehicleCompound of the present invention0.030.031Plasma or lung tissueInhalationDMA+HS-15(Solutol) +Saline*Dosage is calculated based on free base. (DMA: dimethylacetamide; HS-15(Solutol): polyethylene glycol-15-hydroxystearate; saline: physiological saline)

[0552] Plasma sampling: before and after the administration, blood was taken from the orbits of the rats under isoflurane anaesthesia, and placed in an EDTAK 2 centrifuge tube. Centrifugation was performed at 6000 rpm at 4°C for 10 min, and the plasma was collected. Time points for plasma collection comprise 0, 0.0833, 0.25, 0.5, 1, 2, 4, 7 and 24 h.

[0553] Lung tissue sampling: Animals from each group were euthanised by CO 2 inhalation at 0.25, 0.5, 1, 4, 7 and 24 hours after the administration. Then, the animal was dissected to collect lung tissue, which was rinsed with physiological saline, dried with filter paper, weighed in the balance, kept on wet ice and homogenised within 2 hours using a 6-fold volume (i.e., 6 mL per 1 g of tissue) of homogenisation buffer (50% methanol-water).

[0554] Before analysis and detection, all samples were stored at -60°C. The samples were analysed quantitatively by LC-MS / MS. Table 4-1 Pharmacokinetic parameters of test compounds in rats (inhalation administration)Test compoundLung AUC 0-t (h.ng. mL -1< )Lung AUC 0-t / plasma AUC 0-t Lung Cmax (ng / mL)Compound 3-13626652979Compound 4-1246277.12352Compound 6-151736592825Compound 17-1202148.41754Compound 19-1122482452842Compound 31-160897.91183Compound 35-15432 / 2545Compound 36-11013349.14067Compound 37-13281 / 1729Compound 38-1 / 83.61743Compound 45-1450043.42846Control compound 122029.1273

[0555] Conclusion: The compounds of the present invention, such as the example compounds, have good exposure levels and / or lung-to-plasma ratios in the lungs of rats after inhalation administration.5. Test for hERG potassium ion channel Experimental platform: Electrophysiological manual patch-clamp system

[0556] Cell line: Chinese hamster ovary (CHO) cell lines stably expressing hERG potassium ion channel

[0557] Experimental method: In CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, whole cell patch-clamp technique was used to record hERG potassium channel current at room temperature. The glass microelectrode was made of a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after filling the liquid in the electrode was about 2-5 MΩ. The glass microelectrode can be connected to the patch-clamp amplifier by inserting the glass microelectrode into an amplifier probe. The clamping voltage and data recording were controlled and recorded by the pClamp 10 software through a computer. The sampling frequency was 10 kHz, and the filtering frequency was 2 kHz. After the whole cell records were obtained, the cells were clamped at -80 mV, and the step voltage that induced the hERG potassium current (I hERG ) was depolarised from -80 mV to +20 mV for 2 s, then repolarised to -50 mV, and returned to -80 mV after 1 s. This voltage stimulation was given every 10 s, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute). The compound was administered for at least 1 minute at each test concentration, and at least 2 cells (n ≥ 2) were tested at each concentration.

[0558] Data processing: Data analysis processing was carried out by using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition degree of hERG potassium current (peak value of hERG tail current induced at -50 mV) at different compound concentrations was calculated by the following formula: Inhibition % = 1 − I / I o × 100 % where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current after and before the administration, respectively.

[0559] Compound IC 50 was calculated using GraphPad Prism 5 software by fitting according to the following equation: Y = Bottom + Top − Bottom / 1 + 10 ∧ LogIC 50 − X * HillSlope where X represents the Log value of the tested concentration of the test compound, Y represents the percentage inhibition at the corresponding concentration, and Bottom and Top represent the minimum and maximum percentage inhibitions, respectively.

[0560] Conclusion: The compounds of the present invention have no obvious inhibitory effects on the hERG potassium ion channel.6. CYP450 enzyme inhibition test

[0561] The objective of this study was to evaluate the effects of test compounds on the activity of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) by using an in vitro testing system. The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test compounds of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the sample was treated and liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to quantitatively detect metabolites produced by specific substrates, changes in CYP enzyme activity were determined, and IC 50 value was calculated to evaluate the inhibitory potential of the test compound on each CYP enzyme subtype.

[0562] Conclusion: The compounds of the present invention have no significant or only weak inhibitory effects on CYP450 enzymes.7. Pharmacodynamic study on relaxation of thoracic aortic vascular rings in SD rats

[0563] Male SD rats, 8 weeks old and of SPF grade, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The animals were acclimatised for at least one week upon arrival at the animal facility. Prior to the experiment, the rats were weighed and randomly assigned to groups based on body weight. On the day of the experiment, the rats were deeply anesthetised with Zoletil 50 (20 mg / kg, i.p.) and Xylazine (8 mg / kg, i.p.). The thoracic cavity was quickly opened, and the aorta was carefully isolated. A segment of the descending aorta was excised and placed in a petri dish containing a K-H solution saturated with carbogen (95% O 2 +5% CO 2 ). After removing connective tissue surrounding the vessel, vascular rings of approximately 3-5 mm in length were prepared. The vascular rings were suspended using custom-made hooks in an isolated tissue perfusion bath containing a 37°C K-H solution. The bath was aerated with carbogen, and connected to a force transducer (Chengdu Instrument Factory, JZ101H). The force transducer was connected to a multichannel electrophysiological signal recording system (Chengdu Instrument Factory, RM6240E). The vascular rings were rinsed with a K-H solution and equilibrated for 90 minutes under a resting tension of 3 g. Subsequently, the vascular rings were pre-contracted with 10 -6< M norepinephrine in the bath until a stable tension was achieved. The test compound was then added to the bath in a cumulative concentration-gradient manner (from low to high) to induce vasodilation, with a 5-minute interval between each addition. The changes in tension of the thoracic aortic vascular rings were observed. The percentage of relaxation was calculated for each concentration.

[0564] Conclusion: The compounds of the present invention, such as the example compounds, have significant vasodilatory effects in rat thoracic aortic vascular rings.8. SHR rat telemetric blood pressure monitoring

[0565] Surgical implantation of blood pressure telemetry transmitter: one day prior to surgery, the DSI transmitter was sterilised by immersion in a 2% glutaraldehyde solution for 8-10 h; animals were weighed, and anesthetised with Xylazine (8 mg / kg, i.p.) and Zoletil 50 (20 mg / kg, i.p.); and the animals were fasted overnight before the procedure. The implantation procedure was performed on Day 1 of the study, as detailed below. The abdominal skin was aseptically disinfected, and a longitudinal incision was made. The abdominal organs were dissected to expose the abdominal aorta. The pressure-sensing catheter of the transmitter was inserted into the abdominal aorta. Haemostasis and closure of the surgical site were achieved with bioadhesives, and then the transmitter body was secured to the abdominal wall. The muscle and skin layers were sutured, the surgical site was disinfected, and meloxicam was administered subcutaneously for analgesia. Following surgery, the animals were recovered in a 37°C incubator until resumption of voluntary motor activity, and then singly housed in their cages. For the first three postoperative days, the animals received daily subcutaneous injections of gentamicin sulphate (4-8 mg / kg) for infection prophylaxis and meloxicam for analgesia.

[0566] Blood pressure monitoring: After approximately 10 days of postoperative recovery, baseline blood pressure was recorded over a 24-hour period. Rats were assigned to groups based on baseline blood pressure. Following grouping, the rats were administered (either orally or via IT). After a single administration, blood pressure was monitored for 24 hours, during which changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were recorded. Raw data were used to calculate the mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean heart rate at regular intervals (conventionally set at 30 minutes). A p-value of less than 0.05 was considered statistically significant.

[0567] Conclusion: The compounds of the present invention, such as the example compounds, have significant blood pressure-lowering effects in rats, while no significant reduction in abdominal aortic pressure was observed following the IT administration.

Examples

example 1

Example 1 :

[0071]

Step 1: Preparation of 1A

[0072]Compound isobutyryl chloride (7 g, 65.67 mmol) was dissolved in THF (40 mL), and the mixture was cooled to -70°C. A solution of potassium tert-butoxide in tetrahydrofuran (72 mL, 1 N) was slowly added. After the addition, the mixture was naturally warmed to room temperature and stirred for 10 min, and then 100 mL of water and 50 mL of methyl tert-butyl ether were added sequentially. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was directly used in the next step.

Step 2: Preparation of 1B

[0073]Compound 1A (7.77 g, 53.89 mmol) was dissolved in THF (80 mL), and the mixture was purged three times with nitrogen and cooled to -70°C. A solution of LDA in tetrahydrofuran (80 mL, 1 N) was slowly added dropwise. After the addition, the mixture was further stirred for 30 min, warmed to 0°C and then st...

example 2

[0099]

Step 1: Preparation of 2A

[0100]Compound diethyl 2-(dicyanomethyl)-2-methylmalonate (CAS: 1350855-72-9) (1 g, 4.20 mmol), S-methylisothiourea sulphate (0.79 g, 4.2 mmol) and potassium bicarbonate (1.68 g, 16.78 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was warmed to 80°C, stirred overnight and cooled to room temperature. 30 mL of ethyl acetate was added, and the mixture was washed with 20 mL of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5-1 / 2) to obtain compound 2A (0.9 g, yield: 76%).

[0101]LCMS m / z = 283.20 [M+H] +<

Step 2: Preparation of 2B

[0102]Compound 2A (0.9 g, 3.19 mmol) was dissolved in methanol (5 mL). A solution of ammonia in methanol (10 mL, 7 N) was added, and the mixture was warmed to 40°C, stirred overnight, cooled to room temperature and concentrated unde...

example 3

[0119]

Step 1: Preparation of3A

[0120]Pyridazine (3 g, 37.50 mmol) was dissolved in chloroform (60 mL). Trifluoromethanesulphonic anhydride (12.59 g, 44.63 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h. Trimethylsilyl cyanide (15.81 g, 159.26 mmol) was added, and the mixture was warmed to 60°C, reacted for 3 h and cooled. Then, N-methyl morpholine (4.93 g, 48.75 mmol) was added, and the mixture was warmed to 60°C again, reacted overnight and cooled to room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and extracted twice with DCM. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1-1 / 13) to obtain compound 3A (2.5 g, yield: 63%).

[0121]LCMS m / z = 106.20 [M+H] +<

Step 2: Preparation of 3B hydrochloride

[0122]Compound 3A (2 g, 19.03 mmol) was dissolved in...

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, characterised in that< / b> the compound is a compound represented by general formula (I), wherein R is selected from or Z is selected from CH or N; Z1 or Z2 is each independently selected from CH or N, and at least one of Z1 and Z2 is N; X1 or X2 is each independently selected from O or S; A is selected from C3-12 carbocyclyl or 4- to 12-membered heterocyclyl; R1 is -M-(CR1aR1b)r-(CR1cR1d)s-COOH; M is selected from a bond, C3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rm; R2 is selected from C1-6 alkyl or C1-6 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 10 Rk; Q is selected from C3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rq; Ra, Rc, Rm, Rq, Rb3, R1a, R1b, R1c, and R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2, C1-6 alkyl, OC1-6 alkyl, SC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N(C1-6 alkyl)2, -O-C3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C0-4 alkylene-C3-6 carbocyclyl, or -C0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk; alternatively, R1a and R1b or R1c and R1d respectively taken together with the carbon atom to which they are attached form C3-12 carbocyclyl or 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk; Rb1, Rb2, and Rb4 are each independently selected from H, deuterium, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N(C1-6 alkyl)2, -NH-C3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C0-4 alkylene-C3-6 carbocyclyl, or -C0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk; each Rk is independently selected from H, deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C1-6 alkyl, OC1-6 alkyl, SC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NHC1-6 alkyl, N(C1-6 alkyl)2, -O-C3-6 carbocyclyl, -O-3- to 7-membered heterocyclyl, -NH-C3-6 carbocyclyl, -NH-3- to 7-membered heterocyclyl, -C0-4 alkylene-C3-6 carbocyclyl, or -C0-4 alkylene-3- to 7-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C1-6 alkyl, or C1-6 alkoxy; a, c, r, and s are each independently selected from 0, 1, 2, 3, or 4.

2. The compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1, characterised in that A is selected from C3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 Rm; R2 is selected from C1-5 alkyl or C1-4 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 8 Rk; Q is selected from C3-11 cycloalkyl, 4- to 11-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 Rq; Ra, Rc, Rm, Rq, Rb3, R1a, R1b, R1c, and R1d are each independently selected from H, deuterium, halogen, OH, CN, NH2, C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, NHC1-4 alkyl, N(C1-4 alkyl)2, -O-C3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C0-2 alkylene-C3-6 carbocyclyl, or -C0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk; alternatively, R1a and R1b or R1c and R1d respectively taken together with the carbon atom to which they are attached form C3-11 cycloalkyl or 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 Rk; Rb1, Rb2, and Rb4 are each independently selected from H, deuterium, OH, CN, NH2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, NHC1-4 alkyl, N(C1-4 alkyl)2, -NH-C3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C0-2 alkylene-C3-6 carbocyclyl, or -C0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk; each Rk is independently selected from H, deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C1-4 alkyl, OC1-4 alkyl, SC1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, NHC1-4 alkyl, N(C1-4 alkyl)2, -O-C3-6 carbocyclyl, -O-3- to 6-membered heterocyclyl, -NH-C3-6 carbocyclyl, -NH-3- to 6-membered heterocyclyl, -C0-2 alkylene-C3-6 carbocyclyl, or -C0-2 alkylene-3- to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C1-4 alkyl, or C1-4 alkoxy.

3. The compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 2, characterised in that A is selected from C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl; M is selected from a bond, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 Rm; R2 is selected from C1-4 alkyl or C1-3 alkylene-Q, wherein the alkyl or alkylene is optionally substituted with 1 to 6 Rk; Q is selected from C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-10 aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 Rq; Ra, Rc, Rm, Rq, Rb3, R1a, R1b, R1c, and R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or the following groups optionally substituted with 1 to 4 Rk: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, ethenyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; alternatively, R1a and R1b or R1c and R1d respectively taken together with the carbon atom to which they are attached form C3-7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 Rk; Rb1, Rb2, and Rb4 are each independently selected from H, deuterium, OH, CN, NH2, or the following groups optionally substituted with 1 to 4 Rk; methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, morpholinyl, or phenyl; each Rk is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C1-4 alkyl, or C1-4 alkoxy.

4. The compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 3, characterised in that A is selected from the following groups optionally substituted with 1 to 4 Ra: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; M is selected from a bond, or the following groups optionally substituted with 1 to 4 Rm: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R2 is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, or -propylene-Q, wherein the methyl, ethyl, propyl, butyl, methylene, ethylene, or propylene is optionally substituted with 1 to 6 Rk; Q is selected from the following groups optionally substituted with 1 to 4 Rq: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; Ra, Rc, Rm, Rq, Rb3, R1a, R1b, R1c, and R1d are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 Rk; alternatively, R1a and R1b or R1c and R1d respectively taken together with the carbon atom to which they are attached form the following groups optionally substituted with 1 to 4 Rk: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuryl, or tetrahydropyranyl; Rb1, Rb2, and Rb4 are each independently selected from H, deuterium, OH, CN, NH2, or methyl, ethyl, methoxy or cyclopropyl optionally substituted with 1 to 4 Rk; each Rk is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethenyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidyl, piperidyl, pyrazolyl, pyrrolyl, morpholinyl, or phenyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, ethyl, methoxy, or ethoxy.

5. The compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 4, characterised in that A is selected from the following groups optionally substituted with 1 to 4 Ra: phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl; R1 is selected from R is selected from R2 is selected from or Ra, Rc, and Rb3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, methyl, ethyl, methoxy, or cyclopropyl; Rb1, Rb2, and Rb4 are each independently selected from H, deuterium, OH, CN, NH2, methyl, ethyl, methoxy, or cyclopropyl; c is selected from 0, 1 or 2.

6. The compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1, characterised in that the compound has a structure selected from one of those in Table E-1.

7. A pharmaceutical composition, characterised by comprising the compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-6, and a pharmaceutically acceptable carrier, wherein preferably, the pharmaceutical composition comprises 0.01-1500 mg of the compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-6.

8. Use of the compound or the stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating sGC-related diseases.

9. The use according to claim 8, characterised in that the diseases are selected from cardiovascular diseases, kidney diseases or respiratory diseases, preferably pulmonary arterial hypertension, pulmonary hypertension or chronic obstructive pulmonary disease.

10. A method for treating a disease in a mammal, characterised in that the method comprises administering to a subject a therapeutically effective amount of the compound or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-6 or the pharmaceutical composition according to claim 7, wherein the therapeutically effective amount is preferably 0.01-1500 mg, and the disease is preferably cardiovascular diseases, kidney diseases or respiratory diseases.

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